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Principles of Animal Physiology

Moyes Schulte
2e Principles of Animal Physiology
ISBN 978-1-29202-638-1
Christopher D. Moyes
Patricia M. Schulte
9 781292 026381 Second Edition
Principles of Animal Physiology
Christopher D. Moyes
Patricia M. Schulte
Second Edition
Pearson Education Limited
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ISBN 10: 1-292-02638-3

ISBN 13: 978-1-292-02638-1

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Table of Contents

Christopher D. Moyes/Patricia M. Schulte 1
1. Introduction to Physiological Principles
Christopher D. Moyes/Patricia M. Schulte 26
2. Chemistry, Biochemistry, and Cell Physiology
Christopher D. Moyes/Patricia M. Schulte 44
3. Cell Signaling and Endocrine Regulation
Christopher D. Moyes/Patricia M. Schulte 116
4. Neuron Structure and Function
Christopher D. Moyes/Patricia M. Schulte 168
5. Cellular Movement and Muscles
Christopher D. Moyes/Patricia M. Schulte 222
6. Sensory Systems
Christopher D. Moyes/Patricia M. Schulte 274
7. Functional Organization of Nervous Systems
Christopher D. Moyes/Patricia M. Schulte 334
8. Circulatory Systems
Christopher D. Moyes/Patricia M. Schulte 376
9. Respiratory Systems
Christopher D. Moyes/Patricia M. Schulte 440
10. Ion and Water Balance
Christopher D. Moyes/Patricia M. Schulte 500
11. Digestion
Christopher D. Moyes/Patricia M. Schulte 558
12. Locomotion
Christopher D. Moyes/Patricia M. Schulte 606

13. Thermal Physiology
Christopher D. Moyes/Patricia M. Schulte 660
14. Reproduction
Christopher D. Moyes/Patricia M. Schulte 700
Appendix: The International System of Units
Christopher D. Moyes/Patricia M. Schulte 737
Appendix: Logarithms
Christopher D. Moyes/Patricia M. Schulte 739
Appendix: Linear, Exponential, Power, and Allometric Functions
Christopher D. Moyes/Patricia M. Schulte 740
Index 743

action potential A relatively large- adrenal cortex See adrenal gland.
Glossary amplitude, rapid change in the
membrane potential of an excitable
adrenal gland A gland near the
kidney, which in mammals is
cell as a result of the opening and composed of an outermost layer (the
closing of voltage-gated ion channels; adrenal cortex) and an inner layer
A-band (or anisotropic band) The involved in transmitting signals (adrenal medulla).
region of a muscle sarcomere where across long distances in the nervous adrenal medulla See adrenal gland.
the thick filaments occur. system. adrenergic receptors Receptors for
absolute refractory period The period activation energy (Ea) The energetic the catecholamines norepinephrine
during and immediately following an barrier that must be reached before a and epinephrine.
action potential in which an excitable reactant can be transformed into a adrenoreceptors See adrenergic
cell cannot generate another action product. receptors.
potential, no matter how strong the activation gate One of the two gates aerobic Occurring in, or depending on,
stimulus. that open and close voltage-gated the presence of oxygen.
absolute temperature A measure of sodium channels (see also aerobic scope The ratio of the
temperature in kelvins, where 0 K inactivation gate). maximal aerobic metabolic rate to
(absolute zero) is the temperature at active site A region of an enzyme that the basal metabolic rate, typically in
which there is no atomic or binds the substrate and undergoes the range of 3–10.
molecular movement. 1 unit on the conformational changes to catalyze afferent Leading toward a region of
Kelvin scale equals 1° on the Celsius the reaction. interest (see also efferent).
scale. 0 K ⫽ ⫺273°C. active state The phase of a cross- afferent neuron A neuron that
acclimation A persistent but reversible bridge cycle in which myosin is conducts a signal from the periphery
change in a physiological function attached to actin and generating to an integrating center (see also
that occurs as a result of an force. sensory neuron).
alteration in an environmental active transport Protein-mediated affinity A measure of the degree of
parameter, such as temperature or movement of a substance across a attraction between a ligand and a
photoperiod. Acclimation usually membrane with the utilization of molecule that binds the ligand (see
occurs as a result of an experimental some form of energy. Primary active also Km).
manipulation (see also transport uses ATP. Secondary active affinity constant (or Ka) Reciprocal of
acclimatization). transport uses an electrochemical the dissociation constant.
acclimatization A reorganization of gradient (see also facilitated after-hyperpolarization A prolonged
physiological functions that occurs as diffusion, passive transport). hyperpolarization following an action
a result of complex environmental acuity, sensory The ability to resolve potential.
changes, such as season or altitude fine detail of a stimulus. aglomerular kidney A derived form of
(see also acclimation). acute response The rapid phase of kidney, with tubules that lack a
accommodation The process by which response to an external or internal glomerulus, found in many lineages
an eye changes its focal length. change in conditions, usually within of marine fish.
Accommodation allows the eye to seconds to minutes. agonist A substance that binds to a
produce a focused image of objects at adaptation Used in two contexts in receptor and initiates a signaling
different distances. physiology: (1) a change in the event. May include both the natural
acetyl CoA An activated form of genetic structure of a population as a endogenous ligand as well as
acetate that serves as the entry point result of natural selection; (2) a pharmaceutical agents that mimic the
for carbon into the TCA cycle. reversible change in a physiological natural substance.
acetylcholine A neurotransmitter found parameter that provides a beneficial albumen A protein found in eggs that
in most animal species in many types response to an environmental cushions the embryo.
of neurons, including motor neurons change. Evolutionary and albumin A binding globulin (carrier
and the autonomic ganglia of comparative physiologists prefer to protein) that is one of the primary
vertebrates. use only the first definition. proteins of vertebrate plasma; makes
acetylcholinesterase An enzyme that adaptation, sensory See receptor a major contribution to blood osmotic
catalyzes the breakdown of adaptation. pressure.
acetylcholine into choline and adenine A purine nitrogenous base aldosterone Mineralocorticoid
acetate. component of nucleotides, including hormone secreted by the adrenal
acid A chemical that donates a proton nucleic acids. cortex. Its main function is to alter
(see also base). adenosine A nucleoside composed of the levels of Na⫹ and K⫹ in the urine,
acidosis A decrease in pH arising adenine and the sugar deoxyribose, secondarily affecting water transport.
through respiration (respiratory important as a signaling molecule. alkaloids A large group of compounds
acidosis) or metabolism (metabolic adenosine diphosphate (ADP) A derived from plants that have
acidosis). nucleotide composed of the pharmacological effects in animals.
acrosomal reaction The exocytosis of nucleoside adenine with two alkalosis The condition of being
the enzyme-laden acrosomal vesicle phosphate groups, with a single high- alkaline (see also metabolic alkalosis,
of sperm in response to contact with energy phosphodiester bond. respiratory alkalosis).
the ovum. adenosine triphosphate (ATP) A allantoic membrane One of four
acrosome A vesicle in sperm that nucleotide composed of the membranes in an amniote egg.
contains digestive enzymes that nucleoside adenine with three allantoin An intermediate in
enable the sperm to penetrate the phosphate groups, with two high- nucleotide breakdown and uric acid
outer layers of an ovum. energy phosphodiester bonds. synthesis; an important form of
actin G-actin is a monomeric protein adenylate cyclase (adenylyl cyclase) nitrogenous waste for some animals.
that can be polymerized to construct The enzyme that converts ATP to allatostatin A neuropeptide hormone
filamentous actin (F-actin). Actin is cyclic AMP. in arthropods that inhibits the corpus
the basis of both cytoskeletal adhesion plaque A membrane protein allatum from secreting juvenile
microfilaments (composed of the ␣- complex that anchors thin filaments hormone.
actin isoform of G-actin) and skeletal to the membrane. allatotropin A neuropeptide hormone
thin filaments (composed of the ␤- adipose tissue A tissue composed of in arthropods that stimulates the
actin isoform of G-actin) (see also fat cells (adipocytes) that produce corpus allatum to secrete juvenile
myosin). and store lipid. hormone.
actinomyosin The combination of actin ADP See adenosine diphosphate. alleles Different forms of the same
and myosin, joined by a cross-bridge. protein that are encoded by the same

From Principles of Animal Physiology, Second Edition. Christopher D. Moyes, Patricia M. Schulte.
Copyright © 2008 by Pearson Education, Inc. Published by Pearson Benjamin Cummings. All rights reserved.

gene but differ slightly in primary amylase An enzyme that breaks down anus The sphincter through which
sequence. starch (amylose, amylopectin). feces exit the gastrointestinal tract.
allometry (or allometric scaling) The anabolic pathways (or anabolism) aorta The major artery exiting the
pattern seen when comparing Metabolic reactions or pathways that heart.
structural or functional parameters in build complex molecules from aortic body A sensory structure
relation to body size. simpler molecules. located in the vertebrate aorta that
allosteric regulator A molecule that anadromous The life history strategy contains baroreceptors and
binds an enzyme at a site distinct of an animal living most of its life in chemoreceptors.
from the substrate binding site to the sea, then returning to apical The end of a structure opposite
regulate activity. freshwater to reproduce (see also the base.
allosteric site A region of an enzyme, catadromous). apical membrane The end of the cell
distinct from the active site, that anaerobic Without oxygen. Pertains to furthest from the basolateral
binds a molecule other than the an environment without oxygen, or a membrane; the membrane oriented
substrate or product, triggering a pathway that occurs in the absence of away from the circulatory system.
structural change that alters the oxygen (see also aerobic). apnea A period without breathing.
catalytic properties of the enzyme. anaplerotic pathway (or anaplerosis) apocrine A type of secretion whereby
allozyme An allelic variant of an A metabolic reaction that replenishes the cell sheds the apical region of
enzyme. intermediates of pathways. plasma membrane as part of a
␣ adrenergic receptor A G-protein- anastomosis A convergence of two or signaling pathway.
linked cell membrane receptor that more branches of a tubular structure; apoenzyme The proteinaceous part of
binds norepinephrine preferentially, e.g., a direct connection between two an enzyme.
with a lower affinity for epinephrine. arteries in the circulatory system. aquaporin A large tetrameric channel
␣-helix A secondary structure of anatomical dead space The portion of that allows the passage of water
protein or DNA in which the a respiratory structure that cannot through the plasma membrane.
molecule twists in a characteristic participate in gas exchange (e.g., the arginine phosphate A major
pattern, with structure stabilized by trachea and bronchi). phosphagen in invertebrates, which
hydrogen bonds between adjacent androgens Steroid hormones performs the same role as creatine
regions. structurally related to testosterone phosphate in vertebrates.
alternative splicing One of the that control masculine features. aromatase See cytochrome P450
processes that can result in different anemia A condition in which the aromatase.
mRNAs being coded by a single gene. number of erythrocytes or Arrhenius plot A curve relating
Different exons of the gene are hemoglobin in the blood is lower temperature to activity, enabling the
spliced out in each mRNA, resulting than normal. calculation of activation energy.
in a number of possible angiogenesis Synthesis of new blood arteriole A small branch of the arterial
combinations. vessels, often in response to local network immediately preceding a
alveoli (singular: alveolus) The site of hypoxia. capillary bed (see venule).
gas exchange in mammalian lungs. angiotensin A peptide hormone that artery A large blood vessel carrying
ambient External or environmental controls blood pressure. Its precursor blood away from the heart.
conditions, such as ambient is angiotensinogen, which is cleaved asexual reproduction Production of
temperature. by renin to form angiotensin I. This offspring without the fertilization of
amine A class of molecules based on decapeptide is cleaved to the final an ovum by a sperm (see also
ammonia, with a side group form, angiotensin II, an octapeptide. automictic parthenogenesis).
substituting for at least one N atom. angiotensin-converting enzyme (ACE) assimilation Conversion of dietary
amino acid Organic molecules with at An enzyme that converts angiotensin nutrients into metabolizable fuels.
least one amino group and at least I to angiotensin II. assimilation efficiency Proportion of
one carboxyl group. The amino acids anion An ion with a negative charge. dietary nutrients successfully
that are used to build proteins are ␣- anoxic See anaerobic. assimilated.
amino acids. antagonist A substance that binds to a astrocytes Vertebrate glial cells that
ammonia A general term that includes receptor but does not stimulate a help to support and regulate the
both NH3 and NH4⫹ (ammonium), signaling event. Antagonists interfere action of neurons in the central
potent neurotoxins. with the binding of the natural nervous system.
ammoniotele An animal with an ligand. asynchronous muscle A muscle in
excretory strategy in which more than antagonistic controls For a given step which a single neuronal stimulation
half of the nitrogen is excreted as or pathway, sets of controls that exert causes multiple cycles of contraction
ammonia (see also ureotele, uricotele). opposing effects. and relaxation.
amniote Vertebrates with an amnion, antagonistic muscle A muscle that ATP See adenosine triphosphate.
namely reptiles, birds, and opposes the movement of another ATP-binding cassette A common
mammals. muscle. structural motif found in diverse
amphibolic pathway A metabolic anterior pituitary gland The anterior proteins that binds ATP.
pathway that both synthesizes lobe of the pituitary gland of ATPase A class of proteins, including
(catabolic) and degrades (anabolic) vertebrates, also called the enzymes and transporters, that
metabolites. adenohypophysis; secretes tropic couples ATP hydrolysis to a
amphipathic A molecule with both hormones. mechanical or chemical process.
hydrophobic and hydrophilic parts. antidiuretic A substance that induces ATPS Standardized reference condition
amplification An exponential increase a reduction in urine volume. for measuring gas volumes: ambient
in activity from one step of a pathway antifreeze protein A protein that temperature, pressure, and saturated
to the next; typically used in the disrupts the growth of ice crystals, with water.
context of signal transduction allowing an organism to survive atresia The programmed cell death
pathways. subzero temperatures. (apoptosis) of follicles other than the
ampullae of Lorenzini Polymodal antigen A substance, usually a protein, dominant follicle that matures during
receptors that detect both electrical that induces the formation of an the ovulatory cycle.
and mechanical stimuli; found on the antibody that can bind the antigen. atrial natriuretic peptide (ANP) A
nose of sharks. antiport (or exchanger) A transport peptide hormone produced in the
amygdala A part of the limbic system protein that exchanges one ion (or heart that exerts effects on ion and
of the vertebrate brain that is molecule) for another ion (or water balance that tend to reduce
involved in emotional responses such molecule) on the opposite side of a blood pressure. It increases urine
as fear and anger. membrane. volume and Na⫹ excretion.


atrioventricular node (AV node) Part axoneme The microtubule-based taurine; assist in emulsification of
of the conducting pathways of the structure that underlies flagella and lipid within the small intestine.
mammalian heart; delays conduction cilia. binocular vision The ability to
of the electrical signal between the axosomatic synapse A synapse formed compare the images coming from two
atrium and ventricles. between the axon terminal of one eyes to produce three-dimensional
atrium (plural: atria) One of the neuron and the soma (cell body) of perception.
chambers of a heart. Blood moves another neuron. biogenic amine A class of
from the atrium to the ventricle. neurotransmitters derived from
atrophy Loss of tissue mass as a result baroreceptor A receptor that senses amino acids including the
of dying cells; often seen with pressure (by sensing the resulting catecholamines and dopamine.
locomotor muscle in response to stretch on the cell membrane). bioluminescence The production of
prolonged periods of inactivity. basal lamina The extracellular matrix light by living organisms.
August Krogh principle Principle that underlying a sheet of epithelial cells; bipolar neuron A neuron with two
for every biological problem, there is part of the connective tissue formed main processes leading from the cell
an organism on which it can most largely by fibroblasts. body, one of which conveys signals
conveniently be studied. basal metabolic rate (BMR) The toward the cell body, and one of
autocrine A type of cell signaling in metabolic rate of an homeothermic which conveys signals away from the
which a single cell signals another animal at rest, at a thermal neutral cell body.
cell of the same type, including itself. temperature, and post-absorptive blastocoel The cavity formed by the
automictic parthenogenesis (see also resting metabolic rate, inpouching of the blastocyst, which
Production of offspring by a female in standard metabolic rate). eventually forms the alimentary
which the second polar body fuses basal nuclei Interconnected groups of canal.
with the ovum to produce a diploid gray matter within the mammalian blastocyst The hollow sphere of cells
offspring. brain. formed early in embryonic
autonomic division (of the nervous base A molecule that accepts a proton, development.
system) See autonomic nervous or otherwise causes a reduction in bleaching The fading of a
system. proton concentration through effects photopigment following absorption of
autonomic ganglia Ganglia of the on the dissociation of water. energy from photons. In the case of
vertebrate peripheral nervous system. basement membrane See also basal the retinal-opsin complex, absorption
autonomic nervous system Part of the lamina. of energy from light causes retinal to
vertebrate peripheral nervous system basilar membrane The location of the dissociate from opsin. Opsin is not
that controls largely involuntary auditory hair cells in the mammalian pigmented, and thus the
functions such as heart rate. It is cochlea. photopigment loses its color.
divided into three main branches: the basophil A type of white blood cell that blood The circulatory fluid in animals
sympathetic, parasympathetic, and releases histamine; involved in the with closed circulatory systems.
enteric nervous systems. vertebrate immune response. Generally contains proteins, ions,
autotrophy An organism that batch reactor A chemical reactor in organic molecules, and various cell
synthesizes its own nutrients from which nutrients enter and exit types.
inorganic material, using the energy through the same opening; nutrients blood-brain barrier A specialized
of the sun (photoautotroph) or are retained in the reactor and protective barrier made up of glial
inorganic reactions digested; the undigested material is cells that separates the circulatory
(chemoautotrophs). then expelled, and replaced by system and the central nervous
Avogadro’s number The number of another batch of nutrients to be system in vertebrates.
molecules in a mole (6.02252 × 1023). processed. blood vessels Tubes that carry blood
axoaxonic synapse A synapse formed behavioral thermoregulation The use through an animal’s body.
between the axon terminal of one of behavior to control the body blubber Subcutaneous lipid deposits of
neuron and the axon of another temperature of a poikilotherm, or to marine mammals, which provide
neuron (at any point along its length). reduce the costs of thermoregulation thermal insulation.
axodendritic synapse A synapse for a homeotherm. Bohr effect A change in hemoglobin
formed between the axon terminal of ␤-oxidation Pathway of fatty acid oxygen affinity due to a change in
one neuron and the dendrite of catabolism that produces acetyl CoA pH.
another neuron. and reducing equivalents. bolus A volume of material introduced
axon A projection of the cell body of a ␤-sheet Protein folding pattern in into a flow-through system that
neuron that is involved in carrying which stretches of amino acids are moves through the system as a unit,
information, usually in the form of aligned along another amino acid with some dispersion along the way;
action potentials, from the cell body stretch. This secondary structure is often used in the context of a bolus of
to the axon terminal. stabilized by hydrogen bonds. food moving through the
axon hillock The junction between the bilateral symmetry A body form in gastrointestinal tract.
cell body and axon of a neuron. In which the body can be divided by a bombesin A hormone that regulates
many neurons, the axon hillock is the single plane such that the right and release of gastrointestinal hormones
site of action potential initiation, left sides are approximate mirror and control of gastrointestinal
acting as the trigger zone for the images. motility in vertebrates.
neuron. bile A thick, yellow-green fluid bond energy The energy required to
axon terminal The distal end of an composed of salts, pigments, and form a chemical bond.
axon that forms a synapse with an lipids produced by the liver and stored bone In vertebrates, a solid structure
effector cell or neuron. by the gallbladder; when released into composed of mineralized
axon varicosity A type of synapse in the small intestine it neutralizes extracellular matrix of osteocytes;
which the presynaptic cell releases gastric acid and aids in the digestion with cartilage and tendon, it
neurotransmitter at a series of of nutrients, particularly lipids. constitutes the skeleton.
swellings along the axon. bile duct The connection between the book gills The respiratory surfaces of
axonal transport Cytoskeletal- liver and the small intestine. water-breathing chelicerates such as
mediated movement of organelles bile pigments Nondigestible horseshoe crabs.
and vesicles along the length of an breakdown products of porphyrins, book lungs The respiratory surfaces of
axon. including the hemes found in some air-breathing chelicerates such
axonemal dyneins Motor proteins that hemoglobin and cytochromes. as spiders and scorpions.
enable the sliding of microtubules in bile salts Cholic acid conjugated with boundary layer The region of a
cilia and flagella. amino acids, primarily glycine and solution that is in direct contact or


otherwise influenced by a surface; cable properties The electrical carotid rete A network of blood
often called an unstirred layer. properties of axons. vessels that cools the brain.
Bowman’s capsule A cup-shaped calcium-induced calcium release A carrier protein (or binding protein;
expansion of the vertebrate kidney mode of muscle activation where binding globulin) Blood proteins
tubule; surrounds the glomerulus. calcium crossing the sarcolemma that help to transport hydrophobic
brackish water Water that is through a Ca2⫹ channel causes a Ca2⫹ molecules (such as steroid hormones)
intermediate between freshwater and channel in the sarcoplasmic reticulum in the blood.
seawater; typically found in estuaries, to open. carrier-mediated transport All forms
salt marshes, or isolated ponds. caldesmon A calcium-binding protein of transport across membranes that
bradycardia A heart rate that is important in the regulation of smooth require a protein.
slower than normal. muscle contractility. cartilage In vertebrates, a semisolid
brain A large grouping of ganglia that calmodulin A calcium-sensing protein structure composed of the
act as a sophisticated integrating involved in many signal transduction extracellular matrix of chondrocytes:
center. Typically located toward the pathways. the major component of the skeleton
anterior end of the body in the caloric deficit The condition in which of chondrichthians but important in
cephalic (head) region. energy derived from the diet is less other vertebrates as a cushion
brainstem A portion of the vertebrate than energetic expenditure, resulting between joints.
central nervous system that connects in net loss of energy by the animal. catabolic pathway (or catabolism) A
the cerebrum of the brain to the calorie A unit of heat equal to 4.2 metabolic pathway that degrades
spinal cord; contains the pons and joules; nutritional literature may macromolecules into smaller
medulla, the sites of the respiratory refer to the unit Calorie, which is molecules.
and cardiovascular control centers. equivalent to 1000 calories. The unit catadromous A life history strategy of
branchial Relating to gills. of heat required to raise 1 g of water fish (e.g., eels) in which the adult
bronchi (singular: bronchus) Airways at 1 atm by 1°C. migrates from freshwater to seawater
of vertebrate lungs leading from the calorimetry The measurement of heat to breed (see also anadromous).
trachea to the bronchioles. production as an index of metabolic catalysis The progression of a
bronchioles The smallest branches of rate. chemical reaction that proceeds with
the airways of mammalian lungs; calsequestrin A calcium-binding the help of a catalyst.
lead to the terminal alveoli. protein that allows a muscle to catalyst A molecule that accelerates
brood spot A well-vascularized, concentrate Ca2⫹ within the chemical reactions but is not changed
featherless region on the underside of sarcoplasmic reticulum. in the process.
birds that is important for warming cAMP (cyclic AMP) A second catalytic rate constant (kcat) The
developing eggs. messenger produced by adenylate number of reactions catalyzed by a
brown adipose tissue Also known as cyclase; most important action is the single molecule of enzyme per second.
brown fat, a thermogenic tissue stimulation of protein kinase A. catecholamines The biogenic amines
found in many small mammals, often capacitation A maturation step epinephrine and norepinephrine.
in the back or neck region. Abundant experienced by sperm after they cation An ion with a positive charge.
mitochondria in the brown encounter fluids from the female caudal A location near the posterior of
adipocytes possess thermogenin, a reproductive tract. an animal.
protein that uncouples oxidative capillary The smallest of the blood cecum A blind-ended sac that carries
phosphorylation to enhance heat vessels in a closed circulatory system; out digestive reactions in the
production. the site of exchange of materials with gastrointestinal tract.
brush border Abundant microvilli on the tissues. cell body See soma.
epithelial cells in the gastrointestinal carbaminohemoglobin Hemoglobin cell membrane See plasma membrane.
tract, giving the tissue a microscopic bound to carbon dioxide. cellular membranes A general term
brushlike appearance. carbohydrate A group of organic that refers to the collection of
BTPS Standardized reference molecules that share a membranes within a cell, including
conditions for measuring gas preponderance of hydroxyl groups plasma membrane and organelle
volumes: body temperature, (see also disaccharide, membranes.
atmospheric pressure, and saturated monosaccharide, polysaccharide). cellulose A glucose polymer that
with water. carbonic anhydrase (CA) An enzyme serves a structural role in plants;
buccal cavity Mouth cavity. that catalyzes the conversion of indigestible by most animals without
buffer Chemicals which, when placed carbon dioxide and water to the assistance of symbionts.
in solution, confer on the solution an bicarbonate and protons. central chemoreceptors A group of
ability to resist changes in pH when carboxyhemoglobin Hemoglobin chemoreceptors located in the
acid or base is added. bound to carbon monoxide. medulla of vertebrate brains.
bulbourethral gland A mucus- cardiac muscle A form of striated central lacteal A small, saclike vessel
secreting accessory gland of the male muscle that occurs in the heart. in an intestinal villus; collects lipids
reproductive tract. cardiac output The volume of blood that cross the intestinal epithelium.
bulbus arteriosus The outflow pumped by the heart per unit time; central nervous system The portion of
tract of the heart in bony fishes; the product of heart rate and stroke the nervous system containing the
nonmuscular and elastic (see also volume. primary integrating centers. In
conus arteriosus). cardiomyocyte A muscle cell found in vertebrates it consists of the brain
bulk flow The movement of a fluid as a the heart. and spinal cord. In invertebrates, it
result of a pressure or temperature cardiovascular control center A consists of the brain, the major
gradient. region of the brain within the ganglia, and the connecting
bulk phase (or bulk solution) The medulla oblongata that is involved in commissures.
volume of solution that is beyond the regulating heart rate and blood central pattern generator A group of
influence of the surfaces (see also pressure. neurons located in the central
boundary layer). cardiovascular system An alternate nervous system that produce a
bundle of His One of the conducting term for the circulatory system of rhythmic neural output.
pathways of the mammalian heart. animals such as vertebrates. Consists cephalic Toward the anterior end of an
burst exercise High-intensity of the heart, blood, and blood vessels. animal.
exercise powered by glycolytic carotid body A structure located in the cephalization An evolutionary trend
muscle fibers; can continue for only carotid artery leading to the head of toward the centralization of nervous
short periods, until glycogen stores vertebrates; contains baroreceptors and sensory functions at the anterior
are exhausted. and chemoreceptors. end of the body (in the head).


cerebellum A part of the vertebrate cholesterol A steroid compound cloaca The distal portion of the
hindbrain that is involved in produced from isoprene units; hindgut in some fishes, amphibians,
maintaining balance and present in cellular membranes and birds, and reptiles; in these species
coordinating voluntary muscle acts as a precursor for steroid both excretory and reproductive
movement. hormones. products are emitted into the cloaca,
cerebral cortex Outer surface of the cholinergic receptor A receptor that and leave the body via a single
vertebrate brain. binds the signaling molecule opening.
cerebral hemispheres Paired acetylcholine. Cholinergic receptors clonal reproduction A form of asexual
structures of the cerebrum (part of can be divided into nicotinic and reproduction whereby an animal
the vertebrate forebrain). The muscarinic receptors. produces a genotypically identical
cerebral hemispheres are the most chondrocytes The cells that produce offspring (a clone).
obvious structures of a mammalian cartilage. closed circulatory system A
brain. chorion The outer protein layer of an circulatory system in which the blood
cerebral ventricle See ventricle. insect egg; the outer membrane of a remains within a series of enclosed
cerebrospinal fluid (CSF) A fluid vertebrate ovum. blood vessels throughout the
contained within the meninges that chorionic gonadotropin (CG) A third circulation.
surrounds the brain and spinal cord gonadotropin of vertebrates, cochlea Spiral structure in the inner
of vertebrates. produced by the placenta but only in ear of mammals; contains the organs
cerebrum The largest part of the primates. of hearing. Less elaborate, but
mammalian forebrain. chromaffin cells Cells that secrete the present in birds as the cochlear duct.
cGMP See cyclic GMP. hormone epinephrine (adrenaline). In Derived from the lagena of other
cGMP phosphodiesterase An enzyme mammals they are located in the vertebrates.
that cleaves cGMP, producing GMP. compact adrenal medulla, but in coelom The internal compartment of
channel A transport protein that other vertebrates they are more coelomate animals that forms
facilitates the movement of specific dispersed. between two layers of mesoderm.
ions or molecules across a cellular chromophore A molecule that is able coenzymes Organic cofactors.
membrane down an electrochemical to absorb light. In photoreception, coenzyme A A coenzyme derived from
gradient. the chromophore absorbs the energy the vitamin pantothenic acid.
chaperone protein See molecular from incoming photons and cofactors Nonprotein components of
chaperone. undergoes a conformational change, enzymes, including metals,
chemical energy The energy which sends a signal to an associated coenzymes, and prosthetic groups.
associated with the reorganization G protein, in the first step of visual coitus Sexual intercourse.
of the chemical structure of a phototransduction. collagen A trimeric protein found in
molecule. chromosome A single, contiguous extracellular matrix. It interacts with
chemical gradient An area across polymer of DNA found within the other collagen molecules to form
which the concentration of a genome. rigid fibers or durable sheets.
chemical differs, often across a chylomicron A large lipoprotein collecting duct The tube that receives
membrane. complex that carries lipid from the the fluid from the distal tubules of the
chemical synapse A junction between digestive tract through the nephron and empties into the minor
a neuron and another cell in which circulation to processing and target calyx of the kidney.
the signal is transmitted across the tissues. colligative properties Four properties
synapse in the form of a cilia (singular: cilium) Microtubule- of a solute that are due solely to the
neurotransmitter. based extensions from a cell that concentration of solutes, and not
chemoautotroph An organism that move in a wavelike pattern. their chemical nature.
uses inorganic chemical energy to ciliary body A part of the vertebrate colloidal osmotic pressure See oncotic
convert organic sources of carbon eye that secretes the aqueous humor. pressure.
and nitrogen into biosynthetic ciliary muscle The muscle that colon A region of the large intestine
building blocks. controls the shape of the lens of the primarily responsible for water
chemokinetic An increase in vertebrate eye; involved in producing resorption.
nondirectional movement in response a focused image. compatible solute A solute that, at
to the detection of a chemical. ciliary photoreceptors One of two high concentration, does not disrupt
chemoreceptor Used to describe either types of animal photoreceptor cells. protein structure or enzyme kinetics.
a cell containing chemoreceptive Vertebrate photoreceptors belong to competitive inhibition A mode of
proteins, or the proteins themselves. this class (see also rhabdomeric enzyme inhibition in which a
Chemicals such as hormones, photoreceptors). molecule competes with the substrate
odorants, and tastants bind circadian rhythm Regular changes in for the active site on the enzyme;
specifically to chemoreceptor gene expression, biochemistry, competitive inhibitors have the effect
proteins, altering their conformation physiology, and behavior that cycle of reducing the apparent substrate
and causing a signal within the with a period of approximately 24 affinity without affecting Vmax.
chemoreceptor cell. hours. Endogenous circadian compliance A measure of the ability of
chemotaxic Movement toward higher rhythms persist even in constant a hollow structure (e.g., blood vessel,
concentrations of a chemical. darkness. lung) to stretch in response to an
chief cell The secretory cells of the circulatory system A group of organs applied pressure.
gastric epithelium that release and tissues involved in moving fluids compound eye A type of eye seen in
pepsin. through the body; consists of one or arthropods; consists of many
chitin A polymer of N-acetyl more pumping structures and a individual photoreceptive structures.
glucosamine used by arthropods to series of tubes or other spaces conduction Transfer of heat from one
construct the exoskeleton. through which fluid can move. object to another object or a fluid.
chloride cell An ion-pumping cell of citric acid cycle See tricarboxylic acid cone A type of vertebrate
fish gill epithelium (also called a cycle. photoreceptor cell (see also rod).
mitochondria-rich cell). clathrin A triskelion-shaped (three- Cones are typically responsible for
chloride shift The exchange of armed) protein that coats some types color vision in bright light.
chloride and bicarbonate across the of vesicles; vesicle formation begins conformer A strategy whereby the
erythrocyte membrane. with a clathrin-coated pit, which physicochemical properties of an
chlorocruorin A type of hemoglobin enlarges to form a clathrin-coated animal (e.g., temperature and
found in some annelids; known as vesicle. osmolarity) parallel those of the
the green hemoglobins. clearance See renal clearance. environment.


conservation of Km A pattern in which purely by passive means; e.g., heat cytokines Hormones that trigger cell
enzymes from different animals exchange in a rete. division.
share a similar Km when assayed countercurrent multiplier A structure cytoplasm Soluble and particulate
under conditions that approximate in which two fluids flow in opposite interior of a cell, excluding the
those that occur in the animal. directions on either side of an nucleus.
constitutive Usually describes a gene exchange surface, allowing high- cytosine A nucleoside composed of
for a protein that is expressed at efficiency exchange of materials by cytidine and a ribose sugar.
near-constant levels regardless of active means; e.g., ion concentration cytoskeleton Intracellular protein
conditions; can be applied to the in the loop of Henle. network of microtubules,
protein itself, as in “a constitutive covalent bonds Strong chemical bonds microfilaments, and intermediate
enzyme.” involving the sharing of electrons filaments.
continuous-flow stirred-tank reactor between two atoms. cytosol Fluid portion of the cytoplasm,
In gut reactor theory, a type of gut in covalent modification Alteration of a also known as intracellular fluid.
which nutrients flow into the gut macromolecule by the addition (or
where they are mixed with gut removal) of another molecule by Dalton’s law of partial pressures The
contents, and simultaneously the gut forming (or breaking) a covalent total pressure of a gas mixture is the
expels fluids that consist of partially bond; e.g., glycosylation, methylation, sum of the partial pressures of the
degraded nutrients. acetylation, and phosphorylation. constituent gases.
conus arteriosus The outflow tract of cranial nerves A group of vertebrate dead space The portion of the
the heart ventricle in elasmobranchs, nerves that originate in the brain. respiratory system containing gas
lungfish, and amphibians; muscular Vertebrates have 12 or 13 pairs of that does not participate in gas
and valved (see also bulbus cranial nerves depending on the exchange; the sum of the anatomical
arteriosus). species. and physiological dead spaces.
convection Fluid circulation driven by creatine phosphate A high-energy deamination Removal of an amino
temperature gradients; a special case phosphate compound used to store group from a molecule, usually an
of bulk flow. energy and to facilitate its transfer amino acid.
convergence A pattern in a neural from the sites of energy production defecation The expulsion of feces.
pathway in which multiple (mitochondria) to the sites of dehydrogenase A class of enzymes
presynaptic neurons form synapses utilization, such as myofibrils. that involves an exchange of
with a single postsynaptic neuron. cristae The highly convoluted inner electrons between a substrate and
cooperativity A phenomenon membrane of mitochondria. product.
demonstrated by multimeric proteins critical thermal maximum The delayed implantation A reproductive
in which binding of a ligand to one highest environmental temperature strategy in which a fertilized ovum
protein subunit increases the tolerated by an animal. fails to implant in the uterus, thereby
likelihood of binding to other crop milk Produced by some birds, a delaying embryonic growth until
subunits. Seen in vertebrate blood regurgitated slurry of nutrients external conditions are favorable.
hemoglobins. arising from ingested material denature The loss of three-
cornea The clear outer surface of an augmented by secretions. dimensional structure (unfolding) of a
eye. The cornea of an insect cross-bridge The linkage of a myosin complex macromolecule, such as
ommatidium and a vertebrate eye are head to an actin subunit; an protein or nucleic acid.
analogous structures, but they are not essential step in actinomyosin dendrites The branching extensions of
homologous. mechanoenzyme activity. a neuronal cell body that carry
coronary artery Artery that supplies crosscurrent exchanger An exchanger signals toward the cell body.
blood to the heart in vertebrates. in which the flow of the respiratory dendritic A tree-like pattern of
corpus allatum (plural: corpora allata) medium is at an angle to the flow of branching.
A paired neurohemal organ in blood through the exchange surface; dendrodendritic synapse A synapse
arthropods that secretes juvenile seen in bird lungs. formed between the dendrites of two
hormone. crypt of Lieberkühn A pit at the base neurons.
corpus callosum A thick band of axons of intestinal villi. deoxyhemoglobin Hemoglobin that is
that connects the right and left cryptobiosis A dormant state in which not bound to oxygen.
hemispheres of the vertebrate brain. an animal experiences a severe (but deoxyribonucleic acid See DNA.
corpus cardiacum (plural: corpora reversible) metabolic depression depolarization A change in the
cardiaca) A paired neurohemal during adverse conditions. membrane potential of a cell from its
organ in arthropods that secretes cutaneous respiration Gas exchange normally negative resting membrane
adipokinetic hormone. across the skin. potential to a more positive value; a
corpus luteum The remnants of a cuticle The outer layer of the relative increase in the positive
mammalian ovarian follicle that arthropod exoskeleton; composed of charge on the inside of the cell
grows in size and becomes an chitin and proteins. membrane.
endocrine organ that secretes cyclic AMP (cAMP) Cyclic adenosine depolarization-induced calcium release
hormones in support of embryonic monophosphate formed by the action A mode of muscle activation in which
development. of adenylate cyclase; a second calcium crossing the sarcolemma
cortex The surface or outer layer of an messenger that activates protein through a Ca2⫹ channel causes a
organ (e.g., the cortex of the kidney; kinase A. depolarization of the membrane,
the cerebral cortex; cortical bone). cyclic GMP (cGMP) Cyclic guanosine which directly opens a Ca2⫹ channel
cost of transport (COT) The energetic monophosphate formed by the action in the sarcoplasmic reticulum.
cost for an animal to cross a given of guanylate cyclase; a second desmosome A type of cell-cell junction
distance. messenger that activates protein common in epithelial tissues.
cotransporter See symport. kinase G. diabetes mellitus A metabolic
counteracting solutes Pairs of solutes cytochromes Metalloproteins produced condition involving defects in insulin
that act in conjunction to offset the from porphyrins that are central to secretion or signal transduction that
detrimental effects that would arise if many enzymatic reactions, including lead to abnormal regulation of blood
either solute were present alone. the mitochondrial electron transport glucose. There are two main types of
countercurrent exchanger A chain (cytochromes a, a3, b, c) and diabetes mellitus: insulin-dependent
structure in which two fluids flow in cytochrome P450 enzymes. (type 1) and non-insulin-dependent
opposite directions on either side of cytochrome P450 aromatase An (type 2).
an exchange surface, allowing high- enzyme in steroid metabolism that diacylglycerol (DAG, or diglyceride)
efficiency exchange of materials converts androgens to estrogens. A second messenger in the


phosphatidylinositol signaling distal A location furthest from a point can be discriminated by a sensory
system. of reference. Opposite of proximal. receptor.
diadromous A life history strategy of distal tubule The region of a dynein Motor protein that works in
fish that includes movement from vertebrate kidney tubule just before combination with microtubules,
freshwater to seawater to breed the collecting tubules. usually moving in the minus direction
(catadromous) or vice versa disulfide bridge A covalent bond (see also kinesin).
(anadromous). between two sulfhydryl groups, dynein arms The motor proteins that
diaphragm A sheetlike group of denoted as –S–S–; also known as a extend from microtubules in the
muscles that separates the thoracic disulfide bond. axoneme of cilia and flagella.
and abdominal cavities of mammals. diuresis The process of urine dyspnea The sensation of difficulty
diastole The portion of the cardiac formation. with breathing.
cycle in which the heart is relaxing. diuretic An agent that promotes urine
diastolic pressure The arterial blood formation. eccrine gland A type of exocrine gland
pressure during cardiac diastole. dive response A collection of characterized by a long coiled duct
diffusion The net movement of a physiological responses to forced that delivers secretions from the
molecule throughout the available diving in air-breathing animals. secretory region to the surface.
space from an area of high divergence A pattern in a neural ecdysis The periodic shedding of the
concentration to an area of low pathway in which a single exoskeleton of invertebrates
concentration. presynaptic neuron forms synapses (molting).
diffusion coefficient A parameter that with multiple postsynaptic neurons. eclosion The process whereby an adult
reflects the ability of an ion or diving bradycardia A reduction in insect emerges from its cocoon.
molecule to diffuse. heart rate as a result of submergence ectoderm The outermost of the
digastric stomach A two-compartment in air-breathing animals. primary germ layers in a developing
stomach found in ruminants; each of DNA (deoxyribonucleic acid) A embryo that eventually gives rise to
the two compartments is further polymer of nucleotides that acts as tissue such as the nervous system.
divided into two chambers. the genetic template. ectopic pacemaker A pacemaker in an
digestible energy The proportion of DNA microarray A high-throughput abnormal location.
ingested energy that can be further method of analyzing DNA or RNA. ectotherm An animal with body
processed, leaving only indigestible Donnan equilibrium The chemical temperature determined primarily by
material. equilibrium reached between two external factors, including but not
digestion The breakdown of nutrients solutions separated from each other limited to ambient temperature (see
in the gastrointestinal tract. by a membrane permeable to some also endotherm).
digestive enzymes Hydrolytic enzymes of the ions in the solutions. edema Excess accumulation of fluid in
secreted into the lumen of the dopamine A neurotransmitter a tissue.
gastrointestinal tract by the digestive (biogenic amine) produced in various effective refractory period The time
epithelium and accessory glands. regions of the vertebrate brain. period in which an excitable tissue
dihydropyridine receptor (DHPR) The dormancy A general term for cannot be stimulated due to changes
Ca2⫹ channel found in muscle plasma hypometabolic states accompanied in the membrane potential.
membrane, so named because of its by a reduction in activity (see also efferent Leading away from a
ability to bind members of the estivation, hibernation, and torpor). structure; e.g., efferent neurons carry
dihydropyridine class of drugs. dorsal horn A region of gray matter signals from the central nervous
dimer A combination of two within the spinal cord located on the system to the periphery; efferent
monomers, typically in the context of dorsal side. arterioles carry blood away from the
protein structure. A homodimer has dorsal root The dorsal of the two glomerulus of the kidney.
two identical monomers, and a branches of a vertebrate spinal nerve efferent neuron A neuron that
heterodimer has two dissimilar as it enters the spinal cord. Contains conducts impulses from an
monomers. afferent neurons. integrating center to an effector.
dipnoan A group of sarcopterygian fish dorsal root ganglion Clusters of efflux Movement of a substance
commonly called lungfish, most afferent cell bodies of neurons in the outward, usually in the context of
closely related to the fish ancestor of spinal nerves. Located adjacent to the movement out of a cell or tissue.
amphibians. spinal cord. eicosanoids A type of short-lived
dipole A molecule with both partial doubly labelled water An isotopic chemical signaling molecule.
positive (d⫹) and partial negative (d⫺) variant of water (H2O), where a less elasmobranch fish One of two groups
charges resulting from the common isotope is used for both 1H of cartilaginous fish, including skates,
asymmetrical distribution of (2H or 3H) and 16O (18O). Used to rays, and sharks. The other group of
electrons. measure field metabolic rate. cartilaginous fish is holocephalans
direct calorimetry Measurement of down-regulation A decrease in the (ratfish).
heat production; in the context of amount or activity of a protein or elastance A measure of how readily a
animal physiology, a measure of process; e.g., a decrease in receptor structure returns to its original shape
metabolic rate. number or activity on a target cell after having been stretched.
disaccharide A sugar composed of two (see also up-regulation). elastic recoil Movement as a result of
monosaccharides. drag A force that resists the forward the release of elastic storage energy.
discontinuous gas exchange A movement through a fluid through elastic storage energy Energy stored
ventilatory pattern seen in some interactions with the surface of an within a deformed object, which is
insects in which prolonged periods of object. released when the object regains its
apnea are followed by brief but rapid dual breather An animal that can relaxed configuration.
ventilation of the tracheal system. breathe either air or water. Also electrical gradient A charge gradient
dissociation constant (Kd) A measure called a bimodal breather. across a membrane arising from
of the tendency of a complex to duodenum The most proximal region unequal distribution of charged
dissociate into its components; of the small intestine, directly particles.
calculated as the ratio of the product following the stomach. electric organ A trans-differentiated
of the concentrations of the duty cycle In cytoskeletal movement, muscle of fish that generates electric
dissociated components to the the proportion of time in a cross- pulses for detecting objects or
concentration of the complex once bridge cycle that a motor protein defense.
the reaction reaches equilibrium binds its cytoskeletal tract. electrical energy The energy
(e.g., for the reaction AB Δ A ⫹ B, dynamic range The range between the associated with gradients of charged
Kd ⫽ [A][B]/[AB]). minimum and maximum signal that particles.


electrical synapse A junction between eventually gives rise to tissues such and is involved in the stress
neurons in which the signal is as the external surfaces, including response; also called adrenaline.
transmitted as an electrical charge the gut lining. epithelium The outermost cellular
rather than via a neurotransmitter endometrium The innermost layer of layer of eumetazoans.
(see also chemical synapse). the uterus composed of well- equilibrium For a chemical reaction,
electrocardiogram (ECG, EKG) A vascularized epithelial tissue; see also the state in which there is no net
recording of the electrical activity of myometrium. change in the reactants; products and
the heart. endoplasmic reticulum (ER) An substrates continue to interconvert,
electrochemical gradient A gradient intracellular organelle that forms a but at equal rates.
composed of the concentration network through which secretory equilibrium constant (Keq) The mass
gradient of an ion and the membrane products and plasma membrane action ratio of a chemical reaction
potential; the driving force for the components pass. when the reaction is at equilibrium.
movement of that ion across the endoskeleton More commonly referred equilibrium potential The membrane
membrane. to as the skeleton, an internal potential at which an ion is at its
electrogenic A transport process that framework of bones, cartilage, and equilibrium distribution across a
results in a change in electrical tendons that provides support and membrane.
charge across a membrane. resistance for muscular movement. eructation Gaseous release from the
electrolyte A charged solute, such as endosymbiont An organism that lives stomach (belching).
Na⫹, K⫹, and Cl⫺. within another organism. erythrocyte A type of vertebrate blood
electron transport system (ETS) A endosymbiosis A relationship whereby cell that contains hemoglobin (red
series of protein complexes with an organism lives within another cell blood cell).
mobile carriers that produce a proton or organism, and both parties benefit erythropoiesis Production of red blood
gradient across the inner from the relationship. cells from erythroblasts, usually in
mitochondrial membrane. It builds endothelium The innermost layer of specialized erythropoietic tissues.
the gradient by pumping protons as it blood vessels. erythropoietin A hormone released
transfers electrons from reducing endotherm An animal that generates from the kidney that induces
equivalents to oxygen, forming water. and retains heat internally. erythropoiesis.
electroneutral A transport process endothermic reaction A reaction that esophagus The passage from the oral
that does not change the electrical has a positive ⌬H, requiring heat. cavity (mouth) to the stomach.
charge across a membrane. end systolic volume (ESV) The volume essential nutrient A nutrient that
electroreceptor A sensory receptor of blood in the heart at the end of cannot be made by the animal and
that responds to electric fields or systole; the minimum volume of therefore must be obtained from the
discharges. blood that the heart contains during diet.
electrotonic conduction Conduction the cardiac cycle. esterase An enzyme that breaks an
via graded potentials. energetics The study of processes that ester bond.
emergence A phenomenon in which involve the interconversion of energy. estivation A form of dormancy in
the patterns and properties of a energy The ability to do work. which the reduced metabolic rate
complex system are the result of the energy metabolism The sum of occurs in response to dehydration.
interactions of the component parts metabolic reactions that pertain to estradiol-17␤ The dominant estrogen
of that system, and are not the production or utilization of in most species.
necessarily predictable from the energy. estrogens A class of steroid hormones
operation of those components in enteric branch (also enteric division; that act predominantly in females to
isolation. enteric nervous system) Part of the stimulate reproductive maturation
empirical An observation arising from vertebrate autonomic nervous system and control the reproductive cycle.
direct measurement of a parameter. involved in regulating the activity of estrous cycle A reproductive cycle
end diastolic volume (EDV) The the gut. composed of four phases: proestrus,
volume of blood in the heart at the enterosymbiont A symbiotic organism estrus, metestrus, and diestrus.
end of diastole; the maximum volume that lives within the gastrointestinal ethology The study of animal
reached during the cardiac cycle. tract. behavior.
endergonic reaction A reaction that enthalpy The heat content of a system, eupnea Normal breathing.
requires an input of free energy, for symbolized as H. Chemical reactions euryhaline Tolerant of a wide range of
which ⌬G is positive. are often expressed as a change in external salinities, or more precisely
endocardium The internal layer of the enthalpy (⌬H). osmolarities.
heart. entropy A thermodynamic parameter eurytherm An animal that is tolerant
endocrine A signaling pathway in that reflects the degree of disorder in of a wide range of external
which the signaling molecule is a system. temperatures.
released into the blood and affects a environmental estrogen An estrogen- evaporation Volatilization of liquid
distant cell of a different type. like endocrine disruptor. water to gaseous water, with the
endocrine disruptor An enzyme A biological catalyst composed absorption of heat.
environmental chemical (often of protein (sometimes RNA), evaporative cooling The heat loss that
humanmade) that alters cell signaling frequently incorporating a cofactor results when heat is absorbed from
by acting as an analogue or into its structure. the body to enable surface water to
antagonist of an endocrine hormone. enzyme induction An increase in the evaporate.
endocrine gland Type of gland that levels of an enzyme: one way to evolution The process of descent with
secretes hormones into the blood. achieve an increase in catalytic modification, or genetic change in
endocrine system The collective name activity. taxa over time; may be adaptive,
for the group of glands and other eosinophil A type of white blood cell maladaptive, or neutral.
tissues that secrete hormones into that is involved in the immune excess postexercise oxygen
the circulatory system. response to parasites an in allergic consumption (EPOC) A period of
endocytosis Invagination of the plasma reactions. elevated metabolic rate thought to be
membrane resulting in the formation ependymal cells Cells that line the necessary to allow the muscle to
of a vesicle; used to internalize ventricles of the brain. recover from ionic and metabolic
membrane proteins or capture epididymis The structure where sperm disturbances that arose as a result of
extracellular solids (phagocytosis) or mature and are stored in the intense exercise.
liquids (pinocytosis). vertebrate testis. exchanger See antiport.
endoderm The innermost primary epinephrine A catecholamine that can excitable cell A cell that is capable of
germ layer in a developing embryo; act as a hormone or neurotransmitter producing an action potential.


excitation-contraction coupling (or EC fast axonal transport Process by fluorescence Absorbance of a high-
coupling) The processes that link which neurotransmitter-containing energy (low-wavelength) light
external stimulation of a muscle to the vesicles are moved from the cell body followed by release of a lower-energy
activation of actinomyosin ATPase, to the axon terminal of a neuron; (longer-wavelength) light.
resulting in muscle contraction. requires molecular motors. flux Flow of material through a
excitatory postsynaptic potential fast-glycolytic (FG) muscle fibers pathway.
(EPSP) An excitatory potential in a Muscle cells with a biochemical and follicle A multicellular unit composed
postsynaptic cell. mechanical protein profile suited to of somatic tissue surrounding an
excitatory potential A change in the short-duration, high-intensity ovum.
membrane potential in an excitable contractions that rely on glycolysis follicle-stimulating hormone (FSH)
cell that increases the probability of for energy; typically muscle fibers One of the two major gonadotropins
action potential initiation in that cell. that express type IIb myosin. of vertebrates; causes the ovarian
exergonic reaction A reaction that fast-oxidative glycolytic (FOG) muscle follicle to mature.
requires an input of free energy, for fibers Muscle cells with a follicular phase That portion of the
which ⌬G is positive. biochemical and mechanical protein ovulatory cycle where a follicle
exocrine gland A type of gland that profile suited to contraction of matures to release the ovum.
releases its secretions via a duct intermediate duration and intensity; food vacuole A phagocytic vesicle that
(usually into the external rely on a combination of glycolysis fuses with other vesicles and
environment). and oxidative phosphorylation for processing organelles to digest the
exocrine secretions Secretions from energy. Typically muscle fibers that nutrients.
exocrine glands; include chemical express type IIa or II x/d myosin foramen of Panizza A structure that
messengers and substances such as isoforms. connects the left and right aorta in
mucus, slime, and silk. feces The undigested matter expelled the crocodile heart.
exocytosis The transport of vesicles to, from the gastrointestinal tract. forebrain The anterior portion of the
and subsequent fusion with, the feedback A regulatory mechanism vertebrate brain, consisting of the
plasma membrane; serves to secrete whereby a step late in a pathway telencephalon and diencephalon.
vesicle contents into the extracellular causes a change earlier in the Also called the prosencephalon.
space or to introduce proteins into pathway, either decreasing use of the founder effect A phenomenon in
the plasma membrane. pathway (negative feedback) or which the genotypic distribution of a
exon A region of DNA that codes for a increasing its use (positive feedback). population is a result of historical
protein. fever A period of elevated whole body events that caused the population to
exoskeleton An external rigid temperature that arises from an be established by a small number of
structure on the outside of many immune response, typically as a result individuals; often associated with a
invertebrates that serves to restrict of some form of infection. Behavioral reduction in genetic diversity.
the movement of water and provide a fever results when a poikilothermic fovea A small region in the center of
solid framework that controls animal animal responds to an immunological the retina of a vertebrate eye that is
shape and provides resistance challenge by moving into an responsible for high-acuity vision.
needed for locomotion. environment that increases body Frank-Starling effect An increase in
exosymbiont A symbiotic organism temperature. the force of cardiac contraction in
that lives outside the animal. fibroblasts Cells that have a major role response to increasing venous return
exothermic reaction A reaction that in producing the extracellular matrix to the heart.
has a negative ⌬H value, releasing of most soft tissues. free energy The energy in a system
heat. Fick equation The equation relating that is available to do work.
expiration Exhalation. diffusive flux to the energetic gradient freezing-point depression A reduction
extension A movement that causes a (concentration, partial pressure, in the temperature at which a
limb to straighten across a joint, electrical, etc.) driving diffusion. solution freezes; e.g., in the presence
usually caused by contraction of an field metabolic rate (FMR) The of antifreeze molecules.
extensor muscle. metabolic rate of a free-roaming futile cycle A combination of
extensor A muscle that causes a limb animal, usually measured using enyzymatic reactions or processes
to straighten across a joint doubly labelled water. that lead to net breakdown of ATP
(extension). filapodia Thin, fingerlike extensions of and/or release of heat without
external respiration The process by the cell, supported by the actin changes in the carbon substrates.
which animals exchange gases with cytoskeleton.
the environment to supply oxygen to filtrate The solution that passes G protein Type of trimeric membrane
the mitochondria and to remove the through a filter, such as the primary protein, associated with specific
resulting carbon dioxide (see also urine that passes through the transmembrane receptors, that plays
respiration). glomerulus. a role in signal transduction. G
extracellular digestion Breakdown of flagella (singular: flagellum) proteins bind guanine nucleotides;
nutrients in the outside of the cell Microtubule-based extensions from a when bound to GDP the G protein is
resulting from secretion of digestive cell that move in a whiplike pattern; inactive, but when bound to GTP it is
enzymes. usually present alone or in pairs. active. The alpha subunit of the G
extracellular fluids The fluids outside flexion A movement of a limb that protein moves through the
of a cell but contained within the causes the limb to bend at the joint membrane and acts in subsequent
limits of the organism. (caused by a flexor muscle). steps in the signal transduction
extracellular matrix The protein and flexor A muscle that causes a limb to pathway.
glycosaminoglycan network found bend at the joint (flexion). G-protein-coupled receptor A
outside cells; includes cartilage, bone, fluid mosaic model The model of a transmembrane receptor that
and connective tissue. lipid bilayer membrane that includes interacts with a G protein.
extrarenal Occurring in a tissue other multiple types of lipids and proteins GABA (gamma-aminobutyric acid) A
than the kidney. and allows for their free rotation and neurotransmitter; primarily
eye A complex organ that detects light. lateral movement. inhibitory in the vertebrate central
fluidity The degree of free movement nervous system.
facilitated diffusion A mode of of membrane entities within the gallbladder An organ that stores bile
transport in which a protein allows membrane; often assessed using the produced in the liver.
an otherwise impermeable entity to dye DPH, which exhibits an gamete The germ cell of sexually
cross a membrane down its anisotropy that depends on reproducing species; small gametes
electrochemical gradient. membrane fluidity. are sperm and large gametes are ova.


gametogenesis Production of mature glottis A small flap of tissue located inversely proportional to the square
gametes in the ovary or testis. between the pharynx and trachea of root of its molecular mass.
ganglion (plural: ganglia) A cluster of air-breathing vertebrates. granular cells See juxtaglomerular
neuronal cell bodies. Ganglia act as glucagon A hormone produced by the cells.
integrating centers. vertebrate pancreas that inhibits granulosa cells The inner layer of
ganglion cell An interneuron in the glycogen synthesis and stimulates somatic cells of a follicle that
retina of vertebrates. glycogen breakdown, resulting in an surround the primary oocyte.
gap junction Aqueous pore between increase in blood glucose. gray matter Areas of the vertebrate
two cells that allows ions and small glucocorticoids Steroid hormones central nervous system that are rich
molecules to move freely from cell to involved in the stress response that in cell bodies (see also white matter).
cell; formed by proteins called regulate carbohydrate, protein, and growth factor A group of peptide
connexins in the vertebrates and lipid metabolism. hormones that stimulate cells to
innexins in the invertebrates. gluconeogenesis The production of proliferate (hyperplasia) or grow in
gas gland A region of the vasculature glucose from noncarbohydrate size (hypertrophy).
of the swim bladder that secretes precursors; the main part of the growth hormone A peptide hormone
gases. pathway is a reversal of glycolysis, derived from the anterior pituitary
gastric Pertaining to the stomach. enabled by three enzymes that that mediates somatic cell growth.
gastrovascular cavity A space that bypass the two irreversible steps in guanine A purine nitrogenous base
performs the functions of digestion glycolysis. component of nucleotides, including
and circulation; found in organisms glycogen A glucose polysaccharide nucleic acids.
such as cnidarians. that forms the main carbohydrate guanosine A nucleoside of guanine
gene A region of DNA that, when energy store of animals. and a ribose sugar.
transcribed, encodes a protein or an glycogenesis Synthesis of glycogen guanosine triphosphate (GTP) A high-
RNA. from glucose or glycolytic energy phosphate compound in
gene duplication The process of DNA intermediates. energy metabolism; also the
mutation by which a genome can glycogenolysis The breakdown of substrate for guanylate cyclase,
acquire an additional copy of genes. glycogen to form glucose- forming the second messenger cGMP.
generator potential A change in the 6-phosphate. guanylate cyclase Enzyme that
membrane potential in the sensory glycolipid A glycosylated lipid common converts GTP to cGMP in response to
terminal of a primary afferent in the extracellular side of some signaling molecules such as nitric
neuron. It is a graded potential plasma membranes. oxide; has soluble and membrane-
proportional to the signal intensity. If glycolysis The breakdown of bound forms.
it exceeds threshold, it will trigger carbohydrates to form pyruvate, or gustation Detection of ingested
action potentials in the axon of the when oxygen is limiting, other end chemicals: the sense of taste.
sensory neuron. products such as lactate. gustducin A G-protein-coupled
genetic drift A change in gene glycoprotein A protein that has been receptor involved in the sense of taste
frequencies in a population over time modified by the addition of that detects sweet tastants.
as a result of random events. carbohydrates. gut reactor theory Mathematical
genome All of the genetic material of glycosaminoglycan A explanation of the optimal function of
an organism; the complete set of nonproteinaceous component various types of digestive tracts,
DNA in both the nucleus and of the extracellular matrix. modeled after chemical reactors.
mitochondria. glycosuria High levels of glucose in the gyri (singular: gyrus) Wrinkles on the
genotype The specific genetic makeup urine. surface of the brains of many
of an organism. glycosylation The addition of mammals.
germ cell A cell that produces the carbohydrate groups to proteins,
haploid gametes of a sexually lipids, or carbohydrates within the H zone The central region of a
reproducing species. endoplasmic reticulum or Golgi sarcomere corresponding to the
gestation The period of embryonic apparatus. location of the thick filaments where
development within the uterus of a goblet cell A goblet-shaped mucus- there is no overlap with thin
viviparous or ovoviviparous species. secreting cell found in the intestinal filaments; the H zone reduces in size
giant axons Unusually large-diameter and respiratory surfaces. upon contraction.
axons that are present in some Goldman equation The equation that habituation A process by which
invertebrates and vertebrates. predicts the membrane potential repeated stimulation of a neuron
gills Respiratory surfaces that across a cell membrane resulting results in a decreased response.
originate as outpocketings of the from the distribution of multiple ions hair cell Ciliated sensory cells of
body surface; generally used for gas in relation to their permeabilities. vertebrates that react to mechanical
exchange in water. Golgi apparatus An intracellular stimuli (particularly to vibrations).
gland A specialized organ that secretes organelle involved in the processing They are the basis of the senses of
hormones. of proteins prior to export. hearing and balance, and of the lateral
glial cells (glia) A group of several gonadotropin A hormone that line systems of fishes and amphibians.
types of cells that provide structural regulates the activity of reproductive Haldane effect The effect of oxygen on
and metabolic support to neurons. tissues; FSH and LH are the main hemoglobin–carbon dioxide binding.
gliocytes A type of invertebrate glial gonadotropins in vertebrates, and half-life A period of time required for
cell. allatotropin and allatostatin are the half of a population of molecules to
globin The protein component of main gonadotropins in arthropods. be converted to another form; often
hemoglobins. gonads The organs that produce the applied to radioactive decay.
glomerular filtration rate (GFR) The gametes in males (testes) and females heart A muscular pumping structure.
total amount of filtrate per unit time (ovaries). heat The kinetic energy associated with
passing through the glomeruli into graded potential Changes in the the movement of atoms and
the tubules of the kidneys. membrane potential of a cell that molecules.
glomerulus A knot-like cluster of vary in magnitude with the stimulus heat capacity The amount of thermal
capillaries that acts as a biological intensity; results from the opening energy required to increase the
filter in the nephrons of many and closing of ion channels. temperature of 1 g of a substance by
vertebrate kidneys. It permits fluids Graham’s law Describes the rate of 1°C.
and small molecules to pass freely diffusion of a gas in liquid; states that heat of vaporization The heat needed
from the plasma to the tubule the rate of diffusion of a gas is to cause a liquid to become gaseous,
lumen. proportional to its solubility and expressed per unit mass.


heat shock proteins A class of reproductive tissues either hydrophilic A molecule is hydrophilic
molecular chaperones that increase simultaneously or sequentially. (“water loving”) if it dissolves more
in abundance in response to elevated hertz A frequency of 1 per second (1 easily in water than in an organic
temperature; the term includes Hz ⫽ 1 sec⫺1). phase, such as a lipid bilayer.
members of genetically related heterodimer A quaternary structure of hydrophobic A molecule is
proteins that are constitutive and do two dissimilar monomers. hydrophobic (“water hating”) if it
not increase in expression in heterothermy A thermal strategy in dissolves more easily in a lipid phase
response to thermal stress. which the body temperature (TB) than in water.
heater tissues A general term for varies either spatially or temporally. hydrophobic bond Weak interaction
tissues that serve to elevate regional heterotrimeric G protein See G between two nonpolar groups or
or systemic temperature of an animal, protein. molecules arising through their
such as the heater organ of billfish. hexose A general name for mutual aversion to water.
Heliobacter A bacterium that infects monosaccharides with six carbons; hydrostatic pressure Pressure exerted
gastric pits, creating conditions that includes glucose and fructose. by a fluid at rest.
can lead to a gastric ulcer. hibernation A form of dormancy that hydrostatic skeleton A closed water-
hematocrit The proportion of whole occurs as a result of low ambient filled sac that acts as a semisolid
blood that is occupied by red blood temperature and persists for long support for an animal.
cells. periods. hydroxyl ion OH⫺.
heme A metal-binding porphyrin hindbrain The posterior portion of the hypercapnia Higher than normal
derivative that is incorporated into vertebrate brain, consisting of the carbon dioxide levels.
enzymes (e.g., cytochromes) and cerebellum and brainstem. hyperglycemia An elevated blood
nonenzyme proteins (e.g., hippocampus A part of the vertebrate glucose level.
hemoglobin). brain that is involved in the hyperosmotic A solution that has a
hemerythrin An iron-containing formation of memories. higher osmolarity than another
respiratory pigment found in histamine An amino acid; a regulatory solution.
sipunculids, priapulids, brachiopods, molecule that is released from mast hyperplasia An increase in the
and annelids; lacks heme. cells in response to an immunological number of cells in a tissue or organ.
hemimetabolous insect Type of insect challenge. hyperpnea Rapid breathing.
that possesses immature stages histone A protein that reversibly binds hyperpolarization A change in the
(nymphs) that resemble the adults, to DNA, altering its ability to be membrane potential of a cell from its
except in lacking fully formed wings transcribed. normally negative resting membrane
(see also holometabolous insects). holocrine secretion A type of secretion potential to a more negative value; a
hemocoel Collective name for the in which entire cells burst, releasing relative increase in the negative charge
sinuses in the open circulatory their internal contents. on the inside of the cell membrane.
systems of many invertebrates. holometabolous insect An insect in hyperthermia An elevation in body
hemocyanin A respiratory pigment which juvenile stages, dissimilar from temperature (TB) above a desired
found in arthropods and molluscs the adult, undergo dramatic point.
consisting of one or more protein metamorphosis. hypertonic A solution that has a
molecules complexed directly to homeostasis A state of internal combination of osmolarity and solute
copper molecules. constancy that is maintained as a profile that leads to the efflux of
hemocytes Generalized term for blood result of active regulatory processes. water from the cell, resulting in a
cells. Most commonly used for the homeothermy A thermal strategy of an decrease in cell volume.
blood cells of invertebrates. animal (a homeotherm) that has a hypertrophy An increase in the size of
hemoglobin A respiratory pigment relatively constant body temperature cells in a tissue or organ.
consisting of a globin protein (TB). hyperventilation Breathing rate or
complexed to an iron-containing homeoviscous adaptation A process depth that is greater than needed for
porphyrin molecule called heme. whereby cells alter the composition either oxygen supply or carbon
hemolymph The circulatory fluid of of cellular membranes to ensure that dioxide removal.
arthropods. fluidity remains constant to hypocapnia Lower than normal
hemopoietic factor A regulatory compensate for the effects of a carbon dioxide levels.
protein that induces the synthesis of change in the external environment. hypoglycemia Low levels of glucose in
red blood cells; erythropoietin, for homing A movement that returns an the blood.
example. animal to its home range. hypometabolism A period when
Henderson-Hasselbalch equation The homodimer A molecule composed of metabolic rate is lower than the
mass action equation for the two identical subunits. normal resting rate.
dissociation of carbonic acid (H2CO3) homologues Genes that are descended hyposmotic A solution that has a lower
to bicarbonate (HCO3⫺) and hydrogen from a common ancestor, without osmolarity than another solution.
ions (H⫹); important in respiratory intervening duplication events (see hypothalamic-pituitary portal system
physiology. also paralogues). A system of blood vessels within the
Henry’s law One of the ideal gas laws; hormone Type of chemical messenger hypothalamus and pituitary that
describes the dissolution of a gas in a that is carried in the blood and thus carries hypothalamic hormones to
liquid, stating that the amount of gas can act across long distances. the pituitary, where they regulate the
dissolved in a liquid is related to the Classically defined as a substance release of pituitary hormones.
partial pressure and the solubility of released from an endocrine gland hypothalamus A region of the
that gas. and active at very low vertebrate forebrain that is involved
hepatocyte The dominant cell type in a concentrations. in controlling body temperature,
liver. hydration shell A coating of water thirst, hunger, and many other
hepatopancreas An invertebrate tissue bound to the surface of an ion or physiological processes. Regulates
that serves the same roles as the molecule. the function of the pituitary.
vertebrate liver and pancreas. hydrogen bond A class of weak hypothermia A decrease in body
Hering-Breuer reflex A respiratory (noncovalent) bond in which an temperature (TB) below a desired
reflex that reduces breathing in electropositive hydrogen atom is point.
response to overinflation of the lungs; shared by two electronegative atoms. hypotonic A solution that has a
involved in the termination of a hydrolysis The breaking of a covalent combination of osmolarity and solute
breath. bond by introducing a water profile that leads to the influx of
hermaphrodite An animal that molecule; –H is added to one product water into the cell, resulting in an
possesses both male and female and –OH to the other. increase in cell volume.


hypoventilation Breathing rate or inhibitory postsynaptic potential ionic bond A weak bond between an
depth that is less than required for (IPSP) An inhibitory potential in a anion and a cation.
adequate gas exchange. For air postsynaptic cell. ionoconformer An animal with an
breathers this usually involves inner ear A series of membranous internal ion profile that resembles the
insufficient breathing to allow the sacs that contain the organs of ion composition of the external water.
removal of carbon dioxide, rather hearing and balance in vertebrates. ionophore A molecule that forms pores
than insufficient for oxygen supply; inner hair cells One of two types of within membranes, allowing specific
causes elevated blood carbon dioxide hair cells found in the organ of Corti ions to cross.
(hypercapnia) and respiratory in the inner ear of mammals; ionoregulator An animal that
acidosis. involved in the sense of hearing (see maintains an internal ion profile
hypoxemia Lower than normal blood also outer hair cells). independent of the ion composition of
oxygen levels. inorganic ion An ion lacking carbon the external water.
hypoxia Lower than normal oxygen; atoms. ionotropic receptor A receptor protein
usually referring to environmental inositol trisphosphate (IP3) that acts as a gated ion channel.
oxygen levels (see also hypoxemia). A second messenger in the iris A ring of tissue located
phosphatidylinositol signaling immediately in front of the lens of a
I-band (isotropic band) The region of system. vertebrate eye that controls the
a muscle sarcomere where the thin inspiration Inhalation. amount of light entering the eye by
filaments that span a Z-disk do not instar A juvenile form of an insect that altering the size of the pupil.
overlap with the thick filament. resembles the adult form in gross ischemia A reduction in blood flow,
ice-nucleating agent A molecule or appearance. depriving a tissue of oxygen and
particle that initiates the formation of insulation An external or superficial nutrients.
ice at a subfreezing temperature. layer of material that reduces the islets of Langerhans Clusters of
ideal gas law The relationship heat loss from the animal to the endocrine cells in the pancreas that
between pressure, volume, and gas environment, such as fur, feathers, produce the hormones glucagon and
concentration. and blubber. insulin.
ileum The last section of the small insulin Peptide hormone that isocortex The outer layer of the
intestine, connecting the jejunem to homeostatically regulates blood forebrain in mammals.
the large intestine. glucose levels; released in response isoelectric point The pH at which an
imidazole group The amino group to increased blood glucose. ionizable molecule exhibits no net
found in histidine and other integral membrane protein A protein charge.
compounds that exhibits a pK value that is embedded within a cellular isoform A protein that has the same
near physiological pH, and is membrane, and can only be released function as another protein but
therefore important in the buffering with detergent treatment that differs in primary sequence either
of the pH of body fluids. disrupts the membrane. because it is encoded by a different
in situ An in vitro condition in which integrins A class of dimeric gene, or because it results from
the parameter under investigation is transmembrane proteins that is alternative promoter usage or
in a realistic setting. important in the interactions differential splicing (contrast with
in vitro Occurring outside a living betweens cells and the extracellular alleles).
animal or cell. matrix, mediating both adhesion and isometric contraction A muscular
in vivo Occurring within a living cell signalling. contraction that results in force
animal or cell. integument The outer layer of an production without a change in
inactivation gate One of the two gates animal, usually derived from length.
that open and close voltage-gated epithelial cells and their secretions. isopleth A contour line showing the
sodium channels. intercalated disc The intercellular value of a function of two variables
incipient lower lethal temperature contact between cardiomyocytes connecting the points where the
(ILLT) For a poikilotherm composed of gap junctions and function has a particular value; e.g.,
acclimated to a given temperature, it desmosomes. the relationship between pH and
is the lowest temperature that can be intercellular fluid See interstitial bicarbonate concentration as
tolerated. fluid. described by the Henderson-
incipient upper lethal temperature intermediate filaments One class of Hasselbalch equation.
(IULT) For a poikilotherm proteins that are used to make up the isosmotic Describes two solutions with
acclimated to a given temperature, it is cytoskeleton. the same osmolarity.
the highest temperature that can be interneuron A neuron that makes isotonic A solution with a profile and
tolerated. synaptic connections between other concentration of solutes that does not
incus (anvil) One of the three small neurons. result in a change in the volume of a
bones of the mammalian middle ear. internode The region of axonal cell.
indirect calorimetry Estimation of membrane that is covered with the isotonic contraction A muscular
metabolic rate (heat production) myelin sheath. contraction that results in shortening
using consumption of oxygen or interstitial fluid The component of the without force production.
production of carbon dioxide. extracellular fluid that exists between isovolumetric contraction (or
inducible Usually refers to a gene that cells. isovolumic contraction) A phase
can increase in expression in intrinsic protein See integral during the cardiac cycle in which the
response to regulatory conditions; membrane protein. heart contracts, but does not eject
can be applied to the encoded protein intron A region of DNA that is always blood because the valves are closed,
itself, as in “an inducible enzyme.” spliced out of the mRNA following and thus does not change in volume.
inflammation A element of an immune transcription. isozyme An isoform of an enzyme.
response associated with local heat inulin A molecule that is used to assess
production. glomerular filtration rate because it is jejunum An intermediate region of the
ingested energy Term used to describe neither secreted nor recovered by the small intestine, flanked by an
the total energy content of a diet, kidney tubule. anterior duodenum and a posterior
includes both digestible energy and ion An atom or molecule with a net ileum.
indigestible energy. charge. juvenile hormone (JH) A class of
inhibitory potential A change in the ion channels Transmembrane proteins invertebrate hormones derived from
membrane potential that decreases that permit transfer of ions or isoprenes; secreted from the corpus
the probability of action potential molecules through an aqueous pore allatum, JH maintains juvenile
initiation in an excitable cell. down an electrochemical gradient. traits.


juxtaglomerular apparatus A group lateral inhibition Process by which a lipogenesis Conversion of fatty acids and
of cells located near the distal tubule sensory stimulus at one location glycerol to acylglycerides including
and the glomerular afferent inhibits the activity of adjacent monoacylglycerides, diacylglycerides,
arterioles. neurons. Lateral inhibition enhances triglycerides, and phospholipids.
juxtaglomerular cells Secretory cells contrast and improves edge detection lipolysis Breakdown of acylglycerides
of the afferent glomerular arterioles in sensory systems. and phospholipids.
that respond to low blood pressure lateral line system A lipophilic Hydrophobic or nonpolar.
by secreting renin (also known as mechanoreceptive organ in fishes lipoprotein A complex of lipids and
granular cells). and amphibians that senses proteins; central to the transport of
vibrations in the water surrounding lipids between tissues.
kcat See turnover number. the animal. Contains hair cells load A force that opposes muscle
keratan A glycosaminoglycan found in grouped into structures called contraction.
the extracellular matrix. neuromasts. locomotor module A set of
keratin Cytoskeletal protein that leak channel A passive ion channel in musculoskeletal components that
forms one type of intermediate the cell membrane that allows the work together to perform a single
filament; common in hair, nails, and movement of ions down their function, such as flying.
feathers. concentration gradients. long-term potentiation A long-lasting
ketogenesis The production of ketone leaky epithelia An epithelial layer with enhancement of the postsynaptic
bodies. cell-cell connections that permit response as a result of high-
ketolysis The breakdown of ketone paracellular transport. frequency stimulation of the
bodies to form acetyl CoA. lengthening contraction A type of presynaptic neuron.
ketone bodies Substances such as muscle contraction in which external loop of Henle A region of a
acetone, acetoacetate, and ␤- forces cause the muscle to lengthen mammalian kidney tubule that
hydroxybutyrate and other products while force is being generated. connects the proximal and distal
derived from acetyl CoA; produced by length-tension relationship Describes tubule; central to the production of
fatty acid oxidation under food the influence of sarcomere length on hyperosmotic urine.
deprivation conditions. force development in muscle; muscle lower critical temperature (LCT) The
kidney An organ responsible for generates optimal force when lowest environmental temperature at
producing urine, thereby regulating sarcomere length is about 2 µm (in which a homeotherm can survive for
the levels of nitrogenous wastes, most muscles), and tension declines long periods; the lower limit of its
extracellular fluid solute properties, at higher or lower sarcomere lengths. thermoneutral zone.
and osmolarity. lens A clear object that can refract lumen The internal cavity of a
kinesin A motor protein associated light. In the eye, the lens bends multicellular unit, such as a kidney
with microtubules (see also dynein). incoming light rays, helping to form a tubule or gastrointestinal tract.
kinetic energy The energy associated focused image on the retina. lungs Respiratory surfaces that
with movement. leukocytes Vertebrate white blood originate as invaginations of the body
kinocilium The long cilium of a cells; cells in blood that are involved surface. Generally used for gas
mammalian hair cell (involved in the in the immune system. exchange in air.
detection of sound). Leydig cell A testosterone-producing luteal phase The portion of an
Kleiber’s rule The observation that cell interspersed in the interstitium of ovulatory cycle after the follicle has
metabolic rate is related to body the testes. expelled the ovum and before a
mass to the exponent 0.75. ligament A form of connective tissue second follicle matures.
Km See Michaelis constant. that joins two bones. lymph A fluid consisting of an
knockout animal An animal that has ligand A chemical that specifically and ultrafiltrate of blood and immune
been subjected to genetic reversibly binds to a receptor or cells that travels through the
manipulation leading to the inability enzyme. lymphatic system of vertebrates.
to express a native gene. ligand-gated ion channel An ion lymph hearts The pumping structures
Krebs cycle See tricarboxylic acid channel that opens or closes in of the lymphatic system, present only
cycle. response to the binding of a specific in some vertebrates (including fish,
K-type strategy A life history strategy chemical. amphibians, and reptiles).
whereby an animal produces few limbic system A group of structures in lymph nodes Small bean-shaped
offspring and invests heavily in their the vertebrate brain that is involved organs found in various locations in
development (see also r-type in processes including emotions and the lymphatic system of tetrapods;
strategy). memory. they filter lymphatic fluid and
Lineweaver-Burk equation A plot of produce lymphocytes.
lactation Production and release of the reciprocals of reaction velocity lymphatic system In the vertebrates, a
milk from the mammalian mammary (1/V) and substrate concentration network of vessels or sinuses
gland. (1/[S]); generates a linear relationship (depending upon the species) that
lamella A general term referring to a for enzymes with hyperbolic kinetics. carries lymph back to the primary
morphology that resembles stacks of lipase An enzyme that breaks down circulatory system. In many species it
leaves. lipid; includes triglyceride lipases, also performs an immune function.
lamellipodia Flat, sheetlike extensions lipoprotein lipase, and lymphocytes Leukocytes that are
of the cell, supported by the actin phospholipase. involved in adaptive immunity in
cytoskeleton. lipid A class of organic molecules that vertebrates.
laminar flow A pattern in which the share hydrophobicity; includes fatty lysosomes Organelles responsible for
layers of fluid move in parallel, acids, phospholipids, triglycerides, the breakdown of damaged and
usually relative to the surface of an and steroids. unnecessary membranous
object. lipid bilayer The model for a plasma compartments and membrane
larva A pre-adult developmental stage membrane in which the hydrophobic proteins.
that bears little resemblance to the faces of two monolayers of
adult form. phospholipids are associated. macula densa A group of cells in the
latch state A condition in smooth lipid raft A thickened region of the juxtaglomerular apparatus that
muscle in which force is generated plasma membrane; often senses the sodium chloride
with less than expected ATP accumulates cholesterol, concentration of the tubular fluid.
consumption; usually attributed to a phospholipids with long chain fatty macrophage A type of white blood cell
more efficient mechanism of cross- acids, and proteins with long that ingests foreign invaders and
bridge cycling. transmembrane domains. dead or dying cells.


magnetite A crystalline aggregation of when the melting point and the metalloprotein A protein with a metal
a magnetic metal (usually iron); freezing point are not the same ion integrated into its structure;
found in some magnetoreceptors. temperature, this hysteresis suggests enzymatic metalloproteins typically
magnetoreceptor A sensory receptor the presence of a solute that acts in a involve their metal in oxidation-
that responds to magnetic fields. noncolloidal manner, such as an reduction reactions.
malleus (hammer) One of the three antifreeze protein. metamorphosis The transition
small bones of the mammalian membrane fluidity A state that allows between distinct developmental
middle ear involved in transmitting the two-dimensional movement of stages, typically from a larva to an
sound vibrations to the inner ear. lipids and proteins within a lipid adult.
Malpighian tubule The functional bilayer membrane. metazoan A multicellular animal.
equivalent of a kidney tubule in membrane potential The electrical methemoglobin An oxidized form of
insects, releasing the urine into the gradient across a cellular hemoglobin that can no longer carry
gut. membrane. oxygen.
mantle cavity A cavity formed by the membrane recycling The exchange of micelle A lipid monolayer that rolls
body wall (mantle) of molluscs; membrane lipids and protein onto itself to form a sphere with a
generally contains the respiratory between the plasma membrane and hydrophobic inner core and
structures. the internal membrane network. hydrophilic exterior.
mass action ratio Ratio of products to menarche The age at which a female Michaelis constant (Km) The
substrates; when more than one mammal with a menstrual cycle concentration of substrate that yields
product (or substrate) is involved, experiences her first menstruation. half maximal velocity in an enzymatic
their concentrations are multiplied meninges Membranes covering the reaction.
together. When a reaction is at vertebrate central nervous system. Michaelis-Menten equation V ⫽ Vmax
equilibrium, the mass action ratio Mammals have three meninges; × [S]/([S] ⫹ Km).
equals the equilibrium constant (Keq). birds, reptiles, and amphibians have microclimate The external
mass-specific metabolic rate The two; and fish have one. environment within a confined space,
metabolic rate of an animal (usually menses In female mammals, the typically distinct from the broader
described as oxygen consumption) periodic shedding of the endometrial conditions, such as a subterranean
expressed relative to body mass. layer of uterine tissue that occurs if burrow; typically used to describe the
mastication Mechanical disruption of there is no implantation of a fertilized conditions experienced by an
food in an oral cavity (chewing). ovum; also known as menstruation. organism (see also
maximum reaction velocity (Vmax) menstrual cycle The estrous cycle of microenvironment).
The maximal enzymatic rate humans and some other primates. microelectrode A very small electrode
calculated from a substrate-velocity menstruation See menses. used to record electrical signals from
curve; can be estimated by the mesangial cells Contractile cells cells.
enzymatic rate observed when between the capillaries of the microenvironment Like a
product is absent and substrate glomerulus, which control blood flow, microclimate, but can apply to the
concentrations are optimal. and thereby control blood pressure environment surrounding anything
mean arterial pressure (MAP) The within the glomerulus. from individual molecules to whole
weighted average of the systolic and mesencephalon See midbrain. animals.
diastolic pressures, taking into mesoderm The middle of the three microfilaments A polymer of ␤-actin
account the relative length of each of primary germ layers in a developing used to construct the cytoskeleton.
these phases of the cardiac cycle. embryo; eventually gives rise to microglia One of the glial cells of the
mechanical energy A form of energy tissues such as bone, muscle, and vertebrate central nervous system.
arising from the movement or connective tissue. microtubule A large, hollow tube
position of an object; can be either messenger RNA See mRNA. consisting of a polymerized tubulin;
kinetic energy (as in a moving leg) or metabolic acidosis or alkalosis A used to build the cytoskeleton.
potential energy (as in a loaded decrease or increase, respectively, in microtubule-associated protein (MAP)
spring). blood pH as a result of metabolic A protein that binds to microtubules
mechanogated channel (or activity. to alter structural or functional
mechanically gated channel) An metabolic depression A reduction in properties.
ion channel that opens or closes in metabolic rate below resting levels; microtubule-organizing center (MTOC)
response to the stress (or stretch) on associated with a period of A multiprotein complex near the
a membrane. dormancy. center of the cell from which
mechanoreceptor A sensory receptor metabolic flux The flow rate through a microtubules grow.
that detects forces applied to cell metabolic pathway. microvilli Fingerlike extensions from
membranes (such as touch or metabolic rate The rate of heat individual cells, supported by
pressure). Can be used to describe production by a tissue or organism, microfilaments, which serve to
either the receptor protein or cells usually approximated by oxygen increase surface area.
containing these receptors. consumption or carbon dioxide micturition Urination.
medulla oblongata A region of the production. midbrain The middle portion of the
vertebrate brainstem containing metabolic water The water produced vertebrate brain consisting of the
centers that regulate heart rate, by the metabolic breakdown of tectum and tegmentum. Also called
breathing depth and frequency, and macromolecules. the mesencephalon.
blood pressure. Also called the metabolism The sum of all chemical middle ear A part of the vertebrate ear
medulla. reactions in a biologic entity. that consists of the tympanic
medullary cardiovascular center The metabolizable energy The proportion membrane and one or more small
region within the medulla that of digestible energy retained by the bones (in mammals, the incus,
regulates cardiac function. body; the remainder is malleus, and stapes) that help to
medullary respiratory center The unmetabolizable energy lost in amplify sounds.
region within the medulla that excretory products. milieu intérieur The internal
regulates breathing depth and metabolon A group of enzymes that environment of a cell or organism.
frequency. are spatially localized within the cell mineralocorticoids Steroid
melatonin A hormone found in all and perform a function together. hormones involved in water and ion
animal groups that regulates sleep- metabotropic receptor A receptor that balance.
wake cycles. signals via a signal transduction mitochondria Organelles within most
melting point The temperature at pathway (see also ionotropic eukaryotic cells that produce energy
which a solid can become a liquid; receptor). by oxidative phosphorylation;


organized in many tissues as a mucous cells Cells that secrete a myosin light chain A protein that
network or reticulum. complex mucopolysaccharide onto binds the motor protein myosin II,
mitochondria-rich cell Usually refers the surface of a tissue; goblet cells regulating its structure or function.
to the epithelial cells specialized for are a type of mucous cell found in myosin light chain kinase (MLCK) An
ion pumping, which have abundant the intestinal and respiratory enzyme associated with hexameric
mitochondria to meet the energy surfaces. myosin that phosphorylates myosin
demands of active transport (see also mucus A mucopolysaccharide mixture light chain.
chloride cell). secreted from specialized epithelial myosin light chain phosphatase
M-line The midpoint of a sarcomere cells onto the external surface of a (MLCP) An enzyme associated with
where the thick filament lacks tissue. hexameric myosin that
myosin heads. multipolar neurons Neurons with dephosphorylates myosin light chain.
mobile element A region of DNA that many processes leading from the cell myotome A repeating segment in the
can be excised and inserted body; most of these processes are body musculature of adult fish; also,
elsewhere within the genome. dendrites, but one may be an axon. the embryonic form of muscle
molal (molality) Moles of an ion or muscarinic acetylcholine receptors derived from a body segment, or
molecule expressed relative to G-protein-coupled receptors that bind somite.
kilograms of solvent (usually water). acetylcholine. myotube An early stage of muscle
molar (molarity) Moles of an ion or muscle A multicellular tissue differentiation in which multiple
molecule expressed relative to liters composed of myocytes, fibroblasts, myoblasts fuse together to form a
of solvent (usually water). and vascular cells; the contraction of multinucleated contractile tubular
mole 6.02252 × 1023 molecules of a the myocytes leads to force cell.
substance; the molecular weight of a generation or shortening.
substance is the mass of one mole of muscle fiber A single muscle cell; Na⫹/K⫹ ATPase An ion transporter
that substance. can be mononucleated (as in that expels 3 Na⫹ out of a cell and
molecular chaperone A protein that cardiomyocytes) or multinucleated imports 2 K⫹, driven by the energy of
uses the energy of ATP hydrolysis to (as in skeletal muscle fibers). ATP hydrolysis.
help fold or stabilize denatured muscle spindle fiber A muscle stretch nares Nostrils.
proteins; includes heat shock receptor. natriuretic Leading to the appearance
proteins. mutation A heritable alteration in the of sodium in the urine.
molecular phylogeny The evolutionary nucleotide sequence of genomic near-equilibrium reaction A reaction
relationships among organisms as DNA. in which the products and substrates
reconstructed based on molecular myelin See myelin sheath. in vivo are near the concentrations
sequence data. myelin sheath The insulating that would arise if the enzymatic
monoacylglyceride (or monoglyceride) wrappings of vertebrate axons that reaction were to reach equilibrium.
A single fatty acid esterified to a are composed of multiple layers of The reaction is regulated by changes
glycerol molecule. glial cell plasma membrane. in the concentrations of substrates
monocyte A large white blood cell that, Invertebrate axons have analogous and products.
in the tetrapod immune system, wrappings, but they are not generally negative feedback loop A regulatory
ingests foreign particles such as termed a myelin sheath. mechanism whereby a step late in a
microbes; when it leaves the blood myelination The process of forming pathway causes a decrease in the
stream it differentiates into a the myelin sheath around a activity of a step earlier in the
macrophage. vertebrate axon. pathway to reduce the flow through
monogastric stomach An animal that myenteric plexus A network of the pathway.
has a stomach with one (usually neurons found within the smooth nephridium A primitive type of kidney
acidic) compartment. muscle of the gastrointestinal tract tubule found in some invertebrates,
monomer A single subunit of a that controls its muscular and such as annelids and molluscs; can
multimer, such as a dimer or trimer. secretory actions. also refer to the embryonic kidney of
monosaccharide A sugar, usually myoblast A mononucleated, vertebrates.
composed of a 6-carbon (sometimes proliferating cell that can nephron The multicellular unit of the
5-carbon) ring, such as glucose. differentiate to form a muscle cell. kidney, consisting of the tubule and
monounsaturated fatty acid A fatty myocardium The muscle of the heart. the vasculature that serves it,
acid with a single double bond. myocyte A general term for a muscle typically a glomerulus.
monozygotic Arising from a single cell, including smooth muscle cells, Nernst equation An expression that
zygote. cardiomyocytes, and myofibers. describes the ion concentration
motor end plate The location on a myofiber A multinucleated skeletal gradient across a permeable
muscle that forms synapses with a muscle fiber. membrane in relation to the voltage
motor neuron; the muscle side of a myofibril A long bundle of actin, when the system is at equilibrium.
neuromuscular junction. myosin, and associated proteins in nerve A cordlike structure composed
motor neuron A neuron that transmits muscle cells. of a collection of neuronal axons
signals from the central nervous myogenic Muscle contraction initiated grouped together by connective
system to skeletal muscles. by a trigger arising directly within tissues.
motor proteins Mechanoenzymes, such the muscle, as in a myogenic heart. nerve net Description of the
as myosin, that use the energy of ATP myoglobin A type of hemoglobin found structure of the nervous system of
hydrolysis to move along cytoskeletal in muscle. cnidarians.
tracks. myometrium The smooth muscle nervous system Network of neurons
motor unit A group of muscle fibers layers of the uterus. and their supporting cells.
under the control of a single neuron. myosin A large multigene family of net energy The proportion of
mRNA Messenger RNA; the form of ATP-dependent motor proteins that metabolizable energy that is retained
RNA that is used as a template work in conjunction with actin. The by the body, excluding that lost to
during translation to form protein. thick filament of muscle is composed specific dynamic action.
mucin The lipopolysaccharide that is of myosin, which is organized into neurogenic A contraction that occurs
the main component of mucus. hexamers consisting of two myosin in response to a nervous stimulus.
mucosa Refers to the inside layer of a heavy chains (MHC) and four myosin neurogenic muscle A muscle that is
tissue or organ, often that surface light chains (two regulatory MLC and activated by neuronal stimulation.
exposed to the lumen of an organ, two essential MLC). neurohemal organ A region of
such as the gastrointestinal tract (see myosin heavy chain The motor multiple neurons that secrete
also serosa). protein that interacts with actin. hormones into the blood.


neurohormone A chemical messenger formation of ice at subzero orphan receptors Receptors whose
released from a neuron into the temperatures. ligand and function is not known;
blood. nucleoside A molecule composed of a identified based on structural
neuromast A structure consisting of a nitrogenous base (purine or similarity to known receptors.
cup filled with a viscous gel and pyrimidine) linked to a ribose or osmoconformer An animal that
several hair cells; the functional unit deoxyribose sugar. exhibits an internal osmolarity that
of the lateral line system of fishes and nucleotide A nucleoside with one or parallels that of the external
amphibians. more phosphate groups, such as ATP. environment.
neuromuscular junction The synapse nymph The larval form of a osmolarity Analogous to molarity, it is
between a motor neuron and a hemimetabolous insect that resembles the concentration of osmolytes in a
skeletal muscle cell. in most respects the adult form of the solution (osmoles per liter);
neurons (nerve cells) Specialized cells insect, except lacking functional abbreviated OsM.
in the nervous system that wings. osmole One mole of osmotically active
communicate using chemical and solutes.
electrical signals. Many, but not all, obliquely striated muscle A muscle osmolyte An osmotically active solute;
neurons are excitable cells that where striations run obliquely to the any solute that has a significant effect
generate action potentials. axis of shortening. on osmotic pressure.
neuropeptides Polypeptides that act as odorant Molecules that can be detected osmoregulator An animal that exhibits
neurotransmitters. by the sense of smell. an internal osmolarity that is
neurosecretory cell Neurons that odorant binding protein Proteins controlled independently of the
produce and secrete neurohormones found in the mucus of the nasal osmolarity of the external
into the blood, typically in a region epithelium that bind to odorants and environment.
called a neurohemal organ. transfer them to odorant receptors. osmosis The movement of water
neurotransmitter A chemical odorant receptor protein A G-protein- across a membrane from an area
messenger released from a neuron coupled receptor involved in the with a high activity of water to an
into the synaptic cleft. detection of odorants and thus the area with low activity of water.
neutral pH The pH at which the sense of smell. osmotic pressure A force arising due
concentration of H⫹ equals that of olfaction Detection of environmental to the tendency of water to move by
OH⫺. chemicals from outside the body: the osmosis.
neutrophils The most common type of sense of smell. osteoblast A bone precursor cell.
white blood cell in the vertebrate olfactory bulb A part of the vertebrate otolith A small mineralized granule
immune system. forebrain that is involved in (usually calcium carbonate) in the
nicotinic acetylcholine receptors processing olfactory sensations. inner ear of vertebrates. Involved in
Ligand-gated ion channels that open oligodendrocyte A vertebrate glial cell the sense of balance.
in response to acetylcholine binding. that forms the myelin sheath of a outer ear External portion of the
nitric oxide A gaseous neuron in the central nervous vertebrate ear (consisting of the
neurotransmitter and paracrine system. pinna and auditory canal in
chemical signal that is involved in ommatidium The functional unit of the mammals).
regulating many physiological arthropod compound eye. outer hair cells One of two types of
processes; important vasodilator in oncotic pressure The osmotic pressure hair cells found in the organ of Corti
vertebrates. of blood that is due to the in the inner ear of mammals;
nociceptor (or nocioceptor) A sensory concentration of large involved in amplifying sound and
receptor that responds to noxious macromolecules, primarily protein. protecting the inner hair cells from
stimuli of various types (e.g., extreme oocyte One of the intermediate stages loud sounds.
heat or cold, extreme pressure, in the process of producing an ovum oval window Membrane between the
harmful chemicals, tissue damage); during meiosis. middle ear and the inner ear of
pain receptor. oogenesis The production of an ovum. vertebrates. Vibrates to transmit
nocturnal Active at night. oogonia (singular: oogonium) After sound to the inner ear.
node of Ranvier A gap of exposed the primordial germ cell enters the oviparous An animal that produces
axonal membrane between two ovary, it differentiates into an eggs that hatch outside the body.
regions of myelin sheath. oogonium, which undergoes multiple ovoviviparous An animal that holds its
noncompetitive inhibition A mode of rounds of mitosis before entering eggs inside the body until the eggs
enzyme inhibition in which a meiosis. hatch, and then releases active
molecule inhibits an enzyme by open circulatory system A circulatory young.
acting at a site distant from the active system in which the blood passes ovulation The release of an ovum
site; noncompetitive inhibitors can through one or more unbounded following the rupture of a follicle.
increase the Km or reduce the Vmax. spaces called sinuses. ovum The larger of the two gametes of
noncovalent bond Includes four types operculum The stiffened flaplike cover a sexually reproducing species.
of weak bonds that stabilize of the gills of bony fishes. Although an ovum is often defined as
macromolecular structure. opsin A family of G proteins that is the gamete produced by a female, in
nonpolar Having low solubility in involved in visual phototransduction. reality this definition is backward: an
water or other polar solvents. optic chiasm Area in the vertebrate individual is a female if it has gonads
nonshivering thermogenesis (NST) brain where the optic nerves cross. that can produce an ovum.
Production of heat by chemical optic lobe Either of the two lobes of oxidant A molecule that accepts an
means without muscle contraction. the vertebrate midbrain that are electron from another molecule (the
Typically refers to heat production by involved in visual processing; also, in reductant). In doing so, the oxidant
brown adipose tissue; however, there arthropods the regions of the brain becomes reduced.
are other means of NST. involved in processing signals from oxidation A chemical reaction
norepinephrine (or noradrenaline) A the compound eyes. whereby a molecule donates an
catecholamine neurotransmitter; in organ of Corti Located in the cochlea electron to another molecule,
vertebrates, released by the of the inner ear; contains the hair becoming oxidized.
sympathetic nervous system. cells that are involved in the sense of oxidative phosphorylation The process
nuclease An enzyme that hydrolyzes hearing. by which mitochondria produce ATP
nucleic acids; includes DNases and ornithine-urea cycle A pathway by from the oxidation of reducing
RNases. which urea is produced from equivalents (NADH, FADH2). The
nucleator (or nucleating agent) A nitrogen arising from ammonia or electron transport chain expels
molecule or particle that triggers the glutamine. protons from the mitochondria to


produce a proton motive force, which parathyroid glands Glands located on moving blood through the circulatory
is then used by the F1F0 ATPase to the posterior surface of the thyroid systems of some animals.
produce ATP. gland that release parathyroid permeability The ability of a molecule
oxyconformer An animal that exhibits hormones in response to changes in to cross a barrier, such as a
a respiratory rate that declines when extracellular calcium. membrane.
oxygen pressure declines. parathyroid hormone Peptide hormone permease A transporter that mediates
oxygen debt See excess postexercise that regulates blood calcium levels. facilitated diffusion, but is neither a
oxygen consumption. parietal cells The acid-secreting cells channel nor a porin.
oxygen dissociation curve See oxygen within the gastric mucous pH scale A measure of acidity,
equilibrium curve. membrane. expressed as the negative log10 of the
oxygen equilibrium curve A curve parthenogenesis A mode of asexual proton concentration.
showing the relationship between PO2 reproduction whereby offspring are pH-bicarbonate plot (Davenport
and the oxygen saturation of blood produced by a female as a result of a diagram) A graphical depiction of
containing a respiratory pigment. variation on the meiotic pathway. the relationship between the pH and
oxygen carrying capacity The Because meiosis is involved, bicarbonate concentration of a
maximum amount of oxygen that can chromosomal recombination is solution. Usually used to describe
be carried by blood. Includes both possible and the parthenogenic these relationships in arterial blood.
dissolved oxygen and oxygen bound offspring are not clones of the phagocyte A cell that carries out
to respiratory pigments. parent. phagocytosis.
oxygen-transport pigment See respi- partial pressure (of a gas) The phagocytosis The endocytosis of large
ratory pigments. pressure exerted by one of the gases particles from the extracellular space.
oxyregulator An animal that exhibits a in a gas mixture. The sum of the phasic muscle A type of muscle that
constant respiratory rate despite a partial pressures of all the gases in a undergoes rapid contractions and
decline in oxygen pressure. mixture gives the total pressure. relaxations; a twitch muscle.
oxytocin A peptide hormone produced parturition The birthing process by phasic receptor A sensory receptor
by the anterior pituitary; induces the which offspring of viviparous and that produces action potentials only
contraction of smooth muscle during ovoviviparous females are expelled during part of the stimulus (usually at
parturition. from the reproductive tract. stimulus onset and removal).
parvalbumin A Ca2⫹-binding protein phenotype The physical characteristics
P50 The partial pressure at which a in the cytoplasm of some muscles, of an organism; the result of an
respiratory pigment is 50% saturated which buffers Ca2⫹ levels to interaction between the genotype and
with oxygen. accelerate relaxation. the environment.
pacemaker A cell or group of cells passive diffusion A type of passive phenotypic plasticity Production of
whose output of action potentials transport that does not require a different phenotypes by a single
occurs in a rhythmic pattern. protein carrier. genotype as a result of environmental
pacemaker cell An excitable cell that passive transport Movement across a cues; may be reversible or
spontaneously fires action potentials cell membrane without an energy irreversible (see also acclimation).
in a rhythmic pattern. investment other than the chemical pheromones Chemical messengers
pacemaker potentials Spontaneous gradient of the transported molecule; released by an animal into the
depolarizations of the resting includes both passive diffusion and environment that have an effect on
membrane potential that ultimately facilitated diffusion. another animal of the same species.
trigger action potentials within pattern generator A group of neurons phosphagens Energy-rich compounds
pacemaker cells. whose rhythmic firing coordinates a that transfer energy in reactions in
Pacinian corpuscle A type of rhythmic physiological process or which a large change in free energy
vertebrate skin mechanoreceptor. behavior, such as breathing or results when a phosphate bond is
pancreas A vertebrate organ that locomotion. broken.
produces endocrine hormones pentose A five-carbon phosphatase An enzyme that removes
including insulin and glucagon and monosaccharide, such as ribose a phosphate group from a molecule;
also produces exocrine secretions and deoxyribose. important in signal transduction
that are involved in digestion. peptide bond A carbon-nitrogen bond pathways because it reverses the
pancreatic ␤ cells Cells within the (–C–N–); most common in polymers phosphorylations catalyzed by
vertebrate pancreas that secrete the of amino acids. kinases.
hormone insulin. perfusion Movement of fluid through a phosphocreatine See creatine
panting A mode of thermoregulation tissue (e.g., flow of blood through a phosphate.
whereby an increase in the frequency capillary bed). phosphodiester bond –P–O–P–.
of respiration enhances heat loss pericardium The sac surrounding a phosphodiesterase An enzyme that
from the body core. heart. breaks down the phosphodiester
parabronchi Smallest airways of a perilymph The fluid found in the bonds of cyclic nucleotides such as
bird lung. cochlea of the inner ear. cAMP and cGMP.
paracellular transport Passage of peripheral chemoreceptors phosphoglycerides The major class of
solutes or water between cells; in Chemoreceptors located in the aortic phospholipids of biological
most epithelial tissues, tight junctions and carotid bodies of vertebrates that membranes, consisting of a glycerol
and other cell-cell junctions prevent detect changes in blood chemistry. backbone, two fatty acids, and a
paracellular movement of fluids. peripheral membrane protein A polar head group linked to the
paracrine A type of chemical protein that is weakly bound to the glycerol via phosphate.
messenger that is involved in local membrane through an interaction phospholipase An enzyme that breaks
signaling between nearby cells; with a lipid or integral membrane down phospholipids, releasing either
paracrine messengers move through protein. diacylglycerol, polar head groups, or
the interstitial fluid by diffusion. peripheral nervous system (PNS) All fatty acids, depending on the type of
paralogues Genes that are the result of of the neurons outside of the central phospholipase.
a gene duplication event within a nervous system. phospholipids Phosphoglycerides and
lineage (see also homologues). peripheral resistance See total sphingolipids.
parasympathetic nervous system Part peripheral resistance. phosphorylation The addition of a
of the vertebrate autonomic nervous peristalsis The rhythmic contractions phosphate group via a kinase,
system; generally active during of intestinal smooth muscle; involved expending ATP (e.g., a protein kinase
periods of rest; releases acetylcholine in propelling a bolus of food along catalyzes the phosphorylation of a
onto target organs. the gastrointestinal tract and in protein).


phosphorylation potential An plane-polarized light When light porphyrins Organic ring structures
expression of energy status; the mass arrives at a detector, it typically that bind metals, primarily iron but
action ratio for an ATPase reaction exhibits waves that run at all angles. also copper; heme is the most
([ATP]/[ADP][Pi]). Polarizing filters permit the passage common type of porphyrin in
photon The fundamental particle of of light waves that run in a specific animals.
electromagnetic radiation. Streams of angle (plane), generating plane- portal system Two capillary beds
photons can have differing polarized light. connected by a portal vein (e.g.,
wavelengths, in which case the plasma The liquid fraction of hypothalamic pituitary portal system;
resulting radiation is given different vertebrate blood. intestinal liver portal system).
names (e.g., X-rays, gamma rays, plasma membrane The lipid bilayer portal vein A blood vessel that carries
visible light). membrane that encircles a cell. blood from one capillary bed to
photopigments Molecules specialized plasticity The ability to change or another; part of a portal system.
for detecting photons; consist of a remodel a physiological process or positive feedback loop A regulatory
chromophore and an associated structure, as in neural plasticity. See mechanism whereby a step late in a
protein. also phenotypic plasticity. pathway causes an increase in the
photoreceptors Sensory receptors that pleiotropy A phenomenon in which a activity of a step earlier in the
detect photons with wavelengths in single gene is responsible for pathway to increase the flow through
the visible spectrum (i.e., light). Can be multiple, seemingly independent the pathway.
used to describe either the receptor phenotypes. posterior pituitary Lobe of the
proteins or the cells that contain them. pleural sacs A series of membranes pituitary gland; secretes antidiuretic
phototaxis Movement in response to that surround the lungs of hormone and oxytocin; also called
light, either toward (positive vertebrates. The pleural sacs enclose the neurohypophysis.
phototaxis) or away (negative the pleural cavity. postganglionic neuron A vertebrate
phototaxis). plug-flow reactor A type of chemical autonomic neuron has its synapse in
phylogenetic Pertaining to phylogeny. reactor in which the inflow moves the peripheral autonomic ganglia,
phylogeny A hypothesis regarding the as a bolus through the tubelike and extends an axon out into the
evolutionary relationships among reactor. periphery; forms a synapse with a
organisms; can be based on the pN The pH at which a zwitterion has preganglionic neuron.
analysis of various types of data (e.g., no net charge. postsynaptic cell A cell (either a
molecular, morphological). podocyte Cells surrounding the neuron or effector) that receives a
physiological dead space The volume capillaries of the glomerulus, with signal from a presynaptic cell across
of a respiratory organ that is not footlike extensions that form the a synapse.
involved in gas exchange; consists of filtration slits. post-tetanic potentiation (PTP) A
both the anatomical dead space and poikilothermy A thermoregulatory phenomenon in which a postsynaptic
the volume of any regions that, strategy whereby an animal (a cell will respond with an unusually
although capable of acting as gas poikilotherm) allows body large change in membrane potential
exchange surfaces, do not participate temperature (TB) to vary, usually in for several minutes following
in gas exchange (e.g., unperfused or relation to the ambient conditions. repeated action potentials in the
unventilated alveoli). Poiseuille’s equation An equation presynaptic cell.
physoclist Any fish whose swim describing the relationship between potential energy The energy that is
bladder lacks a connection to the gut. the flow, pressure, and resistance of available in a static system; elastic
physotome Any fish whose swim a fluid moving through a rigid tube, storage energy is a form of potential
bladder is connected to the gut via a including the factors influencing energy.
tube. resistance (length, cross-sectional power The rate of doing work.
piloerection The movement of hair or area, and viscosity). power curve The relationship between
feathers perpendicular to the skin in polar See hydrophilic. the velocity of muscle shortening and
response to muscular contraction. polymer A chain of repeating the force of contraction.
pilomotor Related to the nerves and molecules, such as a polysaccharide power stroke The part of a cross-
muscles that change the orientation or a polypeptide. bridge cycle in which structural
of hair. polymodal receptors Sensory receptor changes in myosin alter the relative
pineal complex Consists of the pineal cells that can detect more than one position of the actin flilament.
gland and related structures; type of stimulus. pre-Bötzinger complex The primary
involved in melatonin secretion and polypeptide A chain of amino acids respiratory rhythm generator of
the establishment of circadian linked by peptide bonds. mammals.
rhythms. polyphenism A form of irreversible preferred body temperature The
pinna The cartilaginous structures phenotypic plasticity, generally temperature at which an animal
forming the outer ear of mammals. involving alternative developmental functions best; achieved by
pinocytosis The endocytosis of fluids pathways. physiological mechanisms that alter
by the plasma membrane (see also polypnea Rapid breathing. heat production or loss (mainly in
phagocytosis). polysaccharide A chain of homeotherms) or by behavioral
pit organs The highly sensitive monosaccharides linked by glycosidic choice of habitat (mainly in
thermoreceptive organs of some bonds. poikilotherms).
snakes. polysynaptic Involving more than two preformed water The water that
pituitary gland A hormone-secreting synapses; used in the context of arrives in the diet as a liquid or
organ located at the base of the reflex pathways. trapped within solid foods; distinct
vertebrate brain; connected to the polyunsaturated fatty acid A fatty from metabolic water that is
hypothalamus. acid with two or more double bonds produced during the digestion of
pivotal temperature In an animal with along the carbon chain. foods.
environmental sex determination, it pons A region of the vertebrate brain preganglionic neuron A vertebrate
is a temperature at which equal that communicates information autonomic neuron that has its cell
numbers of males and females result. between the brainstem and the body in the central nervous system
placenta In eutherian mammals, the higher brain centers. Works with the and forms synapses in the peripheral
membrane derived from the medulla to regulate breathing. ganglia.
embryonic chorion that encircles the porin A channel that permits the preprohormone Large inactive
embryo, acting as the interface facilitated diffusion of large polypeptide that is a precursor to a
between embryonic and maternal molecules; e.g., aquaporin is a porin peptide hormone (see also
tissues. that transports water. prohormone).


pressure A force applied to a unit area protein kinase An enzyme that quaternary structure The three-
of a surface. attaches a phosphate to a protein, dimensional arrangement of a
presynaptic cell A neuron that using a molecule of ATP for energy protein composed of multiple
transmits a signal across a synapse and as a phosphate source. monomeric units.
to a postsynaptic cell. protein phosphatase An enzyme that
primary active transport Active removes a phosphate group from a radiant energy Thermal energy
transport that uses chemical or light protein. released from an object in relation to
energy directly, such as an ion- proteoglycan A molecule composed of its temperature.
pumping ATPase; distinct from protein and glycosaminoglycan. radiant heat transfer The emission of
secondary active transport, in which proteolysis The breakdown of thermal energy from a warm object
an entity is driven by electrochemical proteins, usually by hydrolytic to cooler surroundings.
transmembrane gradients of another cleavage of peptide bonds by a radiation The emission of energy from
entity being transported. protease. an object.
primary follicle A follicle that prothoracic glands A pair of ram ventilation A ventilatory strategy
continues to develop to release an endocrine glands that secrete in which the forward movement of
ovum, unlike other follicles that hormones that regulate ecdysis. the animal provides the propulsive
degrade and die during the protofilament A single chain of tubulin force needed for bulk flow of the
maturation process (atresia). that exists prior to the formation of ventilatory medium across the
primary oocyte The products of sheets or microtubules. respiratory surface. Seen in some
oogonia that have undergone the first proton motive force The fishes and insects.
meiotic division to become a diploid electrochemical gradient arising from range fractionation A strategy in
cell that will eventually produce an proton pumping by the mitochondrial which groups of sensory neurons
ovum. electron transport chain. work together to increase the
primary spermatocyte The products protozoans An historical term to dynamic range of a receptor organ.
of spermatagonia that have describe the phyla of early single-celled Each neuron has an overlapping, but
undergone the first meiotic division eukaryotes known now as protists. not identical, dynamic range,
to become a diploid cell that will proximal tubule The region of a allowing a wider range of stimulus
eventually produce a spermatozoan. mammalian or avian kidney tubule intensities to be coded by the
primary structure The sequence of a that lies between the Bowman’s population of receptors.
polymer without consideration of capsule and the descending limb of the rate constant The factor that allows
how it folds; typically refers to the loop of Henle. the prediction of an enzymatic rate
amino acid sequence of a protein. proximate cause The immediate or based on the concentration of the
primary urine The initial contents of direct cause of an organismal substrates.
the lumen of a nephron. In structure, function, or behavior; reaction norm The range of
vertebrates that possess a usually refers to the developmental or phenotypes that can be produced by
glomerulus, the primary urine is the physiological mechanism (see also a given genotype when it is exposed
filtrate. ultimate cause). to different environments.
proboscis A single extension from the pulmonary system A respiratory reactive oxygen species (ROS) A free
head, typically superior to the oral system consisting of lungs and the radical in which the unpaired
opening; the nose. associated vasculature. electron is associated with an oxygen
proenzyme A catalytically inactive pulmonary circuit The part of the atom.
precursor for an enzyme; usually tetrapod circulatory system that receptive field The area of the body
undergoes proteolytic processing to carries blood from the heart to and that, when stimulated by an
become the active enzyme. from the lungs. incoming sensory stimulus, affects
prohormone A polypeptide formed by pupa A developmental stage in the activity of a sensory neuron.
the cleavage of a preprohormone; a hemimetabolous insects that receptor A protein or cell that can
precursor to the formation of a separates the larva from the adult; detect an incoming stimulus.
peptide hormone. can include a period of quiescence. receptor adaptation The process by
prolactin An anterior pituitary pupil An opening in the center of a which sensory receptor cells become
hormone that is responsible for milk camera-type eye through which light less sensitive to sensory signals as
production in mammals, and more enters. signal duration increases.
general roles in ion and water purine A class of nitrogenous bases receptor potential A graded change in
balance in other vertebrates. with two rings; includes guanine and the membrane potential within an
pronephros A simple kidney adenine. epithelially derived sensory receptor
equivalent of larval forms of some Purkinje fibers The terminal branches cell. The receptor potential triggers
amphibians and fish. of the conducting fibers of the the release of neurotransmitter onto
proprioceptor A sensory receptor that mammalian heart. a primary afferent neuron, causing a
provides information about body P wave One of the waveforms of an postsynaptic graded potential. If this
position and movement. electrocardiogram; represents the postsynaptic potential exceeds
prosencephalon See forebrain. depolarization of the atria. threshold, it will trigger action
prostate gland A gland accessory pyloric sphincter The sphincter that potentials in the axon of the primary
associated with the reproductive tract regulates movement of material from afferent neuron.
of male vertebrates. the stomach to the duodenum. recruitment The stimulation of
prosthetic group A nonprotein pyrimidine A class of nitrogenous different collections of muscle fibers
component of an enzyme or other bases with one ring; includes in response to different activity
protein; e.g., a coenzyme (an organic cytosine, thymine, and uracil. patterns.
prosthetic group) or a metal. pyrogen An entity that causes a rectal gland An organ found in
protease An enzyme that breaks homeotherm to mount an immune cartilaginous fish that secretes salt to
peptide bonds of proteins to generate response that culminates in a fever. aid in osmotic regulation.
polypeptides or amino acids. redox balance (reduction-oxidation
proteasome A cytoplasmic Q10 A value that reflects the impact of a balance) A condition in which there
multiprotein complex that degrades 10°C change in temperature on an is no net change in the ratio of
damaged proteins tagged with a enzymatic or metabolic process; also reduced to oxidized reducing
ubiquitin molecule. known as the temperature coefficient. equivalents, typically NADH/NAD⫹.
protein A polymer of amino acids, QRS complex One of the waveforms of redox shuttle A multienzyme
usually folded into complex an electrocardiogram; represents the pathway used to transfer the energy
secondary structures. depolarization of the ventricles. of reducing equivalents from


glycolysis into the mitochondria for produce carbon dioxide (see also responsible for vision in dim light
oxidation. external respiration). (see also cone).
redox status The relative levels of respiratory acidosis or alkalosis Root effect A change in the oxygen
reduced to oxidized molecules of Decrease or increase in blood pH as a carrying capacity of blood as a result
interest; typically applied to result of changes in blood carbon of changes in pH.
metabolic biochemistry (e.g., dioxide (usually as a result of round window Membrane at the end
NADH/NAD⫹) but can also be used to changes in ventilation). of the cochlea; acts as a pressure
reflect the degree of oxidative stress. respiratory chain See electron release for the fluid of the inner ear.
reducing equivalents NAD(P)H or transport system. rRNA The form of RNA that is
FADH2. respiratory pigments Metalloproteins incorporated into the riboprotein
reductant A molecule that donates an that act as oxygen transport and complex known as a ribosome.
electron to another molecule (the storage molecules (e.g., hemoglobin). r-selection A life history strategy
oxidant). In doing so, the reductant respiratory quotient (RQ) The ratio of whereby parents invest minimally in
becomes oxidized. CO2 produced to O2 consumed; large numbers of offspring; best
reduction A chemical reaction indicative of the type of fuel being suited to rapidly exploit underutilized
whereby a molecule accepts an utilized. An RQ of 0.7 indicates fatty niches.
electron from another molecule, acids are the fuel, whereas an RQ of r-type strategy A reproductive
becoming reduced. 1.0 suggests carbohydrates are being strategy where parents produce
reductionism A philosophical oxidized. numerous offspring, with relatively
approach that asserts that complex resting membrane potential The little investment in their care.
processes can be understood in terms membrane potential of an excitable ryanodine receptor A Ca2⫹ channel
of their components. cell when action potentials or found in the sarcoplasmic reticulum
reflex arc A simple neural circuit that graded potentials are not being of muscle, which allows Ca2⫹ to
does not involve the conscious generated. escape into the cytoplasm to initiate
centers of the brain. resting metabolic rate (RMR) The muscle contraction.
reflex control pathway See reflex arc. metabolic rate of an animal at rest
refraction The bending of light as it under experimentally defined saliva A solution of enzymes, salts, and
passes from one medium to another. conditions (see also basal metabolic water secreted into the oral cavity to
refractive index The degree to which rate, standard metabolic rate). lubricate, dissolve, and disrupt food.
a material refracts light. rete mirabile A network of blood salt A neutral molecule composed of
refractory period A period in which vessels that serve to retain heat via an inorganic anion and inorganic
an excitable cell is less likely to countercurrent exchange. cation linked by an ionic bond, such
generate an action potential (see also retina A layer of light-sensitive cells as NaCl (table salt).
absolute refractory period, relative that lines the back of eyes. salt gland An extrarenal gland found
refractory period). retinal A derivative of vitamin A that in some marine and desert
regional heterothermy A acts as the light-absorbing vertebrates that secrete Na⫹ and Cl⫺
thermoregulatory strategy in which chromophore in animal to reduce body salt content.
regions of an animal’s body exhibit photopigments. saltatory conduction The mode of
significantly different temperatures. reversal potential The membrane conduction of action potentials in
regulators Animals that maintain a potential at which there is no net myelinated axons in which action
degree of constancy in an internal movement of an ion through open ion potentials appear to jump from one
physiochemical parameter (e.g., channels. node of Ranvier to the next.
osmolarity or temperature) despite Reynolds number A dimensionless sarcolemma The cell membrane of a
external changes in the parameter. number associated with an object muscle.
regurgitation The expulsion of that reflects how smoothly a fluid sarcomere The contractile unit of
stomach contents back up the flows over the surface of the object. striated muscle, typically measured
esophagus into the oral cavity. rhabdomeric photoceptors One of two from one Z-disk to the next.
relative refractory period A period types of animal photoreceptor cells. sarcomere length The distance
immediately following the absolute Arthropod photoreceptors are between two Z-disks of a sarcomere.
refractory period in which an rhabdomeric (see also ciliary sarcoplasm The cytoplasm of a muscle
excitable cell will generate an action photoreceptors). cell; also known as myoplasm.
potential only if exposed to a rhodopsin A photopigment consisting sarcoplasmic reticulum The
suprathreshold (unusually large) of the protein opsin chemically linked endoplasmic reticulum of muscle.
stimulus. to a vitamin A derivative called satellite cells A population of
relaxed endothermy A thermal retinal. omnipotent stem cells found on the
strategy in which an endothermic rhombencephalon See hindbrain. surface of striated muscle. When
animal allows its body temperature ribonucleic acid See RNA. stimulated, satellite cells can enter
to fall for a period of time. ribosomal RNA See rRNA. myogenesis to repair or replace
renal Pertaining to the kidney. ribosome A complex of RNA and muscle.
renal clearance The removal of an protein that carries out protein saturated (1) For respiratory pigments,
entity from the plasma by the kidney. synthesis. hormone receptors, and carrier
renal tubule Within a nephron, it is rigor A state of skeletal muscle in proteins, refers to a situation in which
the tube composed of a single layer of which cross-bridges remain intact all available proteins are bound to
transport epithelium. because ATP has been depleted from their ligand. (2) For fatty acids, refers
repolarization A return of the the cell. to fatty acid chains that lack double
membrane potential of a cell toward RNA A polymer of ribonucleic acids bonds.
the resting membrane potential similar to DNA except that they saturated fatty acid A fatty acid with
following a depolarization or contain ribose in place of deoxyribose no double bonds.
hyperpolarization. and uracil in place of thymine; scaling The relationship between a
resistance, electrical The force includes mRNA, tRNA, and rRNA. parameter, such as metabolic rate,
opposing the flow of charge through Involved in transferring information and body size.
an electrical circuit. from DNA and in protein synthesis. scaling coefficient The slope of a plot
resistance, vascular The force RNase An enzyme that degrades RNA of log body mass against log
opposing the flow of blood through either from the end (exonuclease) or parameter of interest, such as
the circulatory system. internally (endonuclease). metabolic rate.
respiration The process by which rod A type of vertebrate photoreceptor Schwann cell A type of glial cell in the
mitochondria consume oxygen and cell. In mammals, rods are vertebrates that forms the myelin


sheath around axons in the serum Blood plasma after the clotting sphingolipid One class of phospholipid
peripheral nervous system. factors have been removed. based on a sphingosine backbone.
sclera Tough outer surface of a set point In a homeostatically spinal cord Part of the vertebrate
vertebrate eye. controlled system, the level at which central nervous system extending
sclerites Plate-like sections of an the regulated variable is maintained. from the base of the skull through the
invertebrate exoskeleton. sexual reproduction A process in vertebrae of the spine. The spinal
SDA See specific dynamic action. which two cells (each with half the cord is continuous with the
second messenger A short-lived normal genetic complement as a hindbrain.
intracellular messenger that acts as result of meiosis and recombination) spinal nerves A series of paired nerves
an intermediate in a signal fuse to form one descendant cell. that exit at regular intervals along the
transduction pathway. shivering thermogenesis Heat spinal column.
secondary active transport Transport production through uncoordinated spiracles Small openings leading to the
of a molecule across a membrane stimulation of skeletal muscle respiratory system; spiracles are the
against its electrochemical gradient, contractile units. primary opening to the tracheal
driven by the cotransport of another signal transduction pathways system of insects. The same word is
molecule along its electrochemical Biochemical pathways in which a used for a nonhomologous structure
gradient. change in conformation of a receptor in elasmobranch fishes that provides
secondary structure The folding protein in the target cell is converted an alternate opening for the buccal-
pattern of a macromolecule; an ␣- to a change in the activity of that cell. opercular cavities.
helix is an example of the secondary sinoatrial node (SA node) A remnant spleen A vertebrate organ that is
structure of protein and DNA. of the sinus venosus found at the top involved with the immune, lymphatic,
secretagogue A chemical that induces of the right atrium of the mammalian and circulatory systems. It can act as
the secretion of another chemical, heart. a storage site for red blood cells, and
usually a cell signaling factor such as sinus venosus The chamber leading to removes damaged cells from the
a hormone. the atrium of the heart in circulation. It also generates immune
secretory granules Vesicles of nonmammalian vertebrates. cells called lymphocytes.
secretory product stored within a skeletal muscle A general term to standard conditions Accepted external
cell, prepared for release when the describe the striated muscle that conditions under which physical
cell receives the appropriate signal. works in conjunction with the parameters are assessed; may refer
semicircular canals Structures of the endoskeleton. to pressure, temperature,
inner ear responsible for the sense of sliding filament model A theory that concentration, or other such
balance and body orientation; part of describes the interaction between parameters.
the vestibular apparatus. actin and myosin during cross-bridge standard metabolic rate (SMR) The
seminal vesicles A pair of glands that cycling. metabolic rate of a poikilothermic
store sperm and secrete nutrients smooth muscle A type of muscle that animal at rest and post-absorptive,
and fluids that form the semen, has an irregular arrangement of thick measured at a defined external
emptying it into the vas deferens and thin filaments, and thus lacks temperature. (see also basal
upon ejaculation. sarcomeres. metabolic rate, resting metabolic
semipermeable membrane A sodium-potassium pump See Na⫹/K⫹ rate).
membrane that allows the free ATPase. stapes (stirrup) One of the three
movement of some molecules but solute The particles (ions or molecules) small bones of the mammalian
impedes the movement of others. dissolved in a solution. middle ear.
sensillum (plural: sensilla) Sense solution The fluid in which solutes are Starling curve See Frank-Starling
organs in the insect cuticle. Involved dissolved. effect.
in the senses of taste, smell, touch, solvent The liquid in which solutes are statocyst Hollow, fluid-filled sense
and hearing. dissolved. organ in invertebrates that detects
sensitization A process by which the soma The cell body of a neuron, the orientation of the body with
response of a neuron to a stimulus is containing the nucleus. respect to gravity.
increased. somatic motor division (of the nervous statolith Small dense granule (usually
sensory adaptation See receptor system) The portion of the of calcium carbonate) found in
adaptation. vertebrate peripheral nervous system statocysts.
sensory modality The category of that controls skeletal muscle. steady state A condition in which
sensory input that a sensory system spatial summation The process by there is flux through a reaction or
detects (e.g., light, sound, pressure). which graded potentials at different pathway without a change in the
sensory neuron A neuron that conveys points in the membrane (occurring at concentration of intermediates.
sensory information from the the same time) combine to influence stenohaline An animal that is tolerant
periphery to the central nervous the net graded potential of a cell. of a narrow range of external
system (see also afferent neuron). specific dynamic action (SDA) The salinities.
sensory receptor A tissue, cell, or heat produced during the digestive stenotherm An animal that is tolerant
protein that detects incoming sensory process; also known as the heat of a narrow range of ambient
information. increment. temperatures.
sensory transduction The process of spermatogenesis Production of stereocilia The specialized cilia of
converting incoming sensory spermatozoa. vertebrate hair cells; involved in the
information to changes in cell spermatogonia (singular: sense of hearing.
membrane potential. spermatogonium) After the stereopsis The ability to see in three
series elastic components Elements of primordial germ cell enters the dimensions.
a structure that can store elastic testes, it differentiates into a steroid hormones A large class of
energy when they are deformed. spermatagonium, which undergoes hormones derived from cholesterol.
serosa Referring to the outer layer of a multiple rounds of mitosis before steroids A diverse group of nonpolar
tissue or organ (see also mucosa). entering meiosis. organic molecules composed of
serotonin A neurotransmitter (biogenic spermatozoa The smaller gamete in a multiple carbon rings.
amine) involved in setting mood and sexually reproducing species; stoichiometry The quantitative
regulating blood flow to the brain. sperm. relationship between two entities.
Sertoli cells Elongated cells in the sphincter A ring of smooth muscle that stomach A general term for an
seminiferous tubules of the testis that controls the diameter of an opening, anterior region of a gastrointestinal
nourish the spermatids during controlling passage from one region tract, typically characterized by
spermatogenesis. to the next. acidic digestion processes.


striated muscle A class of muscle that tachycardia Rapid heartbeat. excitable cell to which the membrane
possesses thick and thin filaments tastants Chemicals that are detected must be depolarized in order for an
organized into regular arrays; by the sense of taste. action potential to be initiated.
includes cardiac muscle and skeletal taste bud Structure involved in threshold stimulus The smallest
muscle. gustation in the vertebrates. stimulus that can provoke a response
stroke volume The volume of blood TCA cycle (see tricarboxylic acid in a cell.
pumped by the heart in a single beat. cycle) thyroid hormone An iodine-containing
submucosa The tissue layer that lies tectum Dorsal region of the vertebrate hormone produced by the thyroid
beneath the mucosal layer. midbrain involved in coordinating gland that is involved in the
substrate-level phosphorylation An visual and auditory responses. regulation of metabolism.
enzymatic reaction that produces a teleost fish The most common tidal volume The volume of a
high-energy phosphate. subclass of the bony fishes. respiratory medium moved into or
sulci (singular: sulcus) The folds on temperature coefficient See Q10. out of a respiratory structure during
the surface of the brain in some temporal heterothermy A thermal a single breath.
mammals. strategy whereby a homeothermic tight epithelia An epithelial layer with
summation See spatial summation, animal exhibits periods of cell-cell connections that limit or
temporal summation. poikilothermy, typically to allow a prevent paracellular transport.
supercooling The reduction of reduction in metabolic rate; also tight junction A type of intercellular
temperature of a fluid below its known as relaxed endothermy. connection that is capable of
freezing point but without the temporal summation The process by preventing the free movement of
formation of ice. which graded potentials occurring at molecules between the cells.
surface tension The force of adhesion slightly different times combine to tissue An aggregation of related cells
that binds molecules of a fluid influence the net graded potential of linked together by various types of
together at the interface with air. the cell. intercellular connections.
surfactant Substance that lowers the tendon The connection between a titin A very large protein that runs
surface tension of liquids; secreted in muscle and a bone. along the thin filament in striated
the lungs of vertebrates. tension, muscular The force produced muscle, determining its length and
swim bladder A gas-filled organ that by a contracting muscle. orienting into the sarcomere.
fish use for buoyancy compensation. terminal cisternae An enlargement of tonic muscle A muscle type with a
sympathetic division See sympathetic the sarcoplasmic reticulum near the slow contraction that persists for long
nervous system. muscle plasma membrane, periods (see also phasic muscle).
sympathetic nervous system Part of specifically T-tubules. tonic receptor A receptor that
the vertebrate autonomic nervous tertiary structure The three- produces action potentials
system; active during periods of dimensional structure of a throughout the duration of a
stressful activity; releases the macromolecule, stabilized by stimulus.
neurotransmitters epinephrine and numerous weak bonds. tonicity The property of an
norepinephrine onto target organs. tetanus The sustained contraction of a extracellular solution that determines
symport A transporter that carries two muscle arising from multiple whether a cell will swell or shrink.
or more entities across a cell stimulations in close succession. torpor A type of dormancy
membrane in the same direction; thalamus One of the basal ganglia of characterized by a relatively short
also known as a cotransporter. the vertebrate brain that relays period of hypometabolism.
synapse The junction between a sensory information to the cerebral total lung capacity The volume of air
neuron and another neuron or cortex. in the lungs at the end of a maximal
effector cell; consists of a presynaptic theca The outer layer of somatic cells inspiration; the maximum amount of
cell, the synaptic cleft, and a surrounding a follicle, separated from air that can be held in the lungs.
postsynaptic cell. the inner granulosa cells by a basal total peripheral resistance The net
synaptic cleft The extracellular space lamina. resistance of the vasculature.
between a presynaptic cell and a thermal conductance The transfer of totipotent stem cell An embryonic cell
postsynaptic cell at a synapse. thermal energy either within an that has the capacity to differentiate
synaptic depression A decrease in object or from one object to another. into any type of cell when given the
neurotransmitter release in response thermal energy Energy associated appropriate cell signaling information.
to repeated action potentials. with heat production. trabeculae Any partition that divides
synaptic facilitation An increase in thermogenesis Heat production. or partially divides a cavity.
neurotransmitter release in response thermogenin The mitochondrial trachea (plural: tracheae) The single
to repeated action potentials. uncoupling protein found in large airway leading to the paired
synaptic plasticity The capacity of mammalian brown adipose tissue. bronchi of vertebrate lungs; also, the
synapses to change their structure thermoneutral zone The range of nonhomologous respiratory
and function. ambient temperatures over which an structures that are the main
synaptic transmission The process of animal does not need to alter conducting airways in arthropod
transmitting information across a metabolic processes to maintain tracheal systems.
neural synapse. internal constancy. tracheal system The respiratory
synaptic vesicles Neurotransmitter- thermoreceptor A sensory receptor structures of insects and some other
containing vesicles that release that responds to temperature. groups of air-breathing arthropods.
neurotransmitter into a synapse. thermoregulation The physiological tracheoles The terminal structures of
synergism A situation in which two strategy an animal uses to control arthropod tracheal systems across
agents or processes have a combined temperature within the desired which gas exchange takes place.
effect greater than the sum of the range. transcellular transport Movement of
effects of the two agents or processes thick filament A polymer of about 300 solutes or water across a cell layer
applied individually. myosin dimers that produces the through the cell itself, typically
systemic circuit The part of the contractile force in muscle. crossing both apical and basolateral
tetrapod circulatory system that thin filament A muscle-specific ␣-actin cell membranes.
carries blood from the heart to the polymer similar in structure to a transcription RNA synthesis using the
body and back. microfilament; serves as a framework DNA template of a gene.
systole The phase of the cardiac cycle that translates actinomyosin activity transducin An inhibitory G protein
in which the heart is contracting. into force generation. involved in visual signal transduction
systolic pressure The arterial blood threshold potential The critical value in the vertebrates.
pressure during systole. of the membrane potential in an transfer RNA See tRNA.


transgenic animal An animal that has tubulin The monomeric protein unitary displacement The distance a
been genetically modified to possess subunit of microtubules, itself a single motor protein moves during a
a heritable mutation. dimer of ␣-tubulin and ␤-tubulin. cross-bridge cycle.
transition state A temporary, turbulent flow A disordered pattern of unsaturated fatty acid A fatty acid
intermediate state in the fluid flow over the surface of an with one or more double bonds.
conversion of substrate to product object that reduces the efficiency of upper critical temperature The
when a molecule obtains enough movement of the object through the highest temperature at which a
energy to reach the activation fluid. homeothermic animal can live for
energy barrier. turnover number The number of extended periods; the upper limit of
translation Protein synthesis using times a single enzyme molecule the thermoneutral zone.
ribosomes and mRNA template. completes a reaction cycle each U/P ratio The ratio of an ion or
transmembrane receptor A receptor second; also known as the catalytic molecule concentration in the urine
protein that spans the cell constant (kcat ). (U) versus the plasma (P).
membrane; consists of an turnover rate The number of catalytic up-regulation Increase in protein
extracellular domain, a events in a given period of time. For an number or activity in a target cell
transmembrane domain, and an individual enzyme, it is synonymous (see also down-regulation).
intracellular domain. with the catalytic constant (kcat ). It can urea A nitrogenous waste possessing
transmural pressure The pressure also be used to describe the rate of two nitrogen atoms per molecule.
difference across the wall of a synthesis and degradation of a ureotele An animal with an excretory
chamber (e.g., a blood vessel, heart, metabolite, such as ATP. strategy in which urea dominates the
or airway). T wave The portion of an nitrogenous wastes.
transpirational water loss Water loss electrocardiogram (EKG) that ureter The tube connecting the kidney
arising from gas exchange across the represents the repolarization of the to the bladder.
respiratory surface. ventricle. urethra The tube carrying urine from
transpulmonary pressure The twitch fibers Muscle fibers that the urinary bladder to the excretory
difference between the intra-alveolar undergo a rapid opening.
pressure and the intrapleural contraction/relaxation cycle (a uric acid A nitrogenous waste
pressure in mammalian lungs. twitch), in contrast to tonic fibers. possessing four nitrogen atoms per
transverse tubule See T-tubule. twitch muscle A muscle that contracts molecule.
triacylglycerol (or triglyceride) Three and relaxes once after each neuronal uricolytic pathway A pathway of
fatty acids esterified to a glycerol stimulus; a phasic muscle. breakdown of uric acid present in all
molecule. tympanal organ Sensory receptor animals.
tricarboxylic acid cycle The cyclical involved in hearing in insects; insect uricotele An animal with an excretory
mitochondrial pathway that oxidizes ears. strategy in which uric acid is the
acetyl CoA to form 3 NADH, 1 FADH2, tympanic membrane Thin membrane dominant nitrogenous waste.
and 1 GTP; the pathway that that separates the outer ear from the urine A solution of nitrogenous waste
produces most of the CO2 arising middle ear. Helps to transfer sound produced by the kidney or kidney-
from metabolism. vibrations to the inner ear. like tissues.
trichromatic color vision The system
of three different photoreceptors by ubiquitin A small protein that is added van der Waals interactions A type of
which humans and some other to damaged proteins to mark them weak bond forming from the mutual
animals obtain color vision. for degradation by the proteasome. attraction of the nuclei of two atoms
trimer A molecule composed of three UCP See uncoupling protein. in a molecule.
subunits. ultimate cause Why an organism has vas deferens The duct through which
tRNA (or transfer RNA) A cloverleaf- a particular structure, function, or sperm are carried from the sites of
shaped RNA molecule that binds a behavior; usually involves synthesis in the epididymis to the
particular amino acid and understanding the evolutionary ejaculatory opening.
participates in translation, binding to advantage of the trait (see also vasa recta The straight blood vessels
a three-nucleotide sequence of mRNA proximate cause). arranged in a hairpin loop that run
(codon) to transfer the amino acid to ultrafiltration Process of filtration of a from kidney cortex to medulla and
a growing polypeptide. fluid through a size-selective back to the cortex. The countercurrent
trophoblast An outer layer of cells membrane under pressure; used to arrangement allows removal of salts
derived from the mammalian form the primary filtrate of the and water from the peritubule
blastocyst that forms the interface vertebrate kidney. Also causes the interstitium while maintaining
between the fertilized ovum and the formation of lymph from blood in intramedullary osmotic gradients.
uterine wall. vertebrates. vascular endothelium Thin layer of
tropic hormones (or trophic hormones) ultraviolet light Short-wavelength cells that lines blood vessels.
Hormones that cause the release of light (<~300 nm); its high energy can vasculature The blood vessels of the
other hormones. damage macromolecules. circulatory system.
tropomyosin A regulatory protein that uncoupling (of oxidative vasoconstriction Narrowing of a blood
stretches across seven actin phosphorylation) When vessel as a result of contraction of the
monomers in a thin filament, mitochondrial respiration continues vascular smooth muscle; decreases
controlling myosin’s access to its without the production of ATP. local blood flow.
binding site on the thin filament. uncoupling protein (UCP) A class of vasodilation Widening of a blood
troponin A trimeric regulatory protein proteins, which includes thermogenin vessel as a result of relaxation of the
bound to tropomyosin. It responds to (UCP1), that act by dissipating the vascular smooth muscle; increases
high [Ca2⫹] by inducing tropomyosin mitochondrial proton motive force. local blood flow.
to move into a position that allows unipolar neuron A neuron with one vasomotion Change in the diameter of
myosin to bind actin. process leading from the cell body; blood vessels; also known as
T-tubule An extension of the plasma this process generally splits into two angiokinesis.
membrane (sarcolemma) of some branches, one conveying information vasomotor response The changes in
muscles that serves to improve the toward the cell body and one diameter of blood vessels in response
conduction of the action potential conveying information away from the to vasodilatory or vasoconstricting
into the fiber. cell body. factors; also known as the
tubule, renal Also known as a kidney uniporter A class of transporter that angiokinetic response.
tubule, it is the single filtration unit of carries a single entity (ion, atom, vasomotor tone The degree of
the vertebrate kidney. molecule) with each transfer. contraction of the smooth muscles


surrounding the arterioles (see also visual cortex A part of the vertebrate weak bonds Ionic bonds, hydrogen
venomotor tone). brain that is responsible for bonds, van der Waals forces, and
veins Blood vessels that return blood processing visual signals. hydrophobic interactions.
to the heart. In vertebrates, blood visual field The area that is visible to white adipose tissue A lipid storage
flows from the capillaries into an eye, without changing eye tissue of mammals; distinct from
venules and then into veins. position. brown adipose tissue. Other
venomotor tone The degree of vital capacity The maximum amount vertebrates lack brown adipose
contraction of the smooth muscles of respiratory medium that can be tissue, and white adipose tissue is
surrounding the veins (see also moved into or out of the respiratory typically referred to simply as
vasomotor tone). system with each breath. “adipose tissue.”
ventilation Active movement of the vitamin A dietary compound that white matter Areas of the vertebrate
respiratory medium (air or water) serves as a precursor for prosthetic central nervous system that are rich
across the respiratory surface. groups of proteins, particularly in axons (see also gray matter).
ventilation-perfusion ratio (or enzymes. white muscle A muscle fiber type
ventilation-perfusion matching) vitellin The dominant protein found in specialized for rapid, high-intensity
The relationship between the yolk produced from vitellogenin. contractions that continue for a short
ventilation (flow of respiratory vitellogenin The major protein in the duration; usually composed of type
medium) and the perfusion (flow of yolk of an egg. IIb myosin isoforms.
blood) at a respiratory surface. viviparous Animal whose offspring work The transfer of energy that
ventricle A fluid-filled sac or cavity develop internally and are released occurs when force is exerted on a
(e.g., the spaces in the center of the as active young (see oviparous and body to cause it to move.
vertebrate brain; the muscular ovoviviparous). work loop A method used to assess
pumping chambers of the vertebrate Vmax The maximal rate of catalysis by whether a muscle is performing
heart). an enzyme; arises when all positive or negative work.
venule Small blood vessels located substrates are at optimal (saturating)
between capillaries and veins. concentrations and prior to the xeric A dry, dehydrating environment.
vesicle A membrane-bound formation of product.
compartment that buds off from the VO2max The maximal sustainable rate of yolk A deposit of lipid and protein
intracellular membranous network, oxygen consumption exhibited by an (largely vitellin) associated with an
often encased in coat proteins such as animal. The experimental means to ovum.
clathrin. assess VO2max differs among
vestibular apparatus The organ of disciplines. Z-disk The protein plate at the end
balance in the vertebrates. volatile fatty acids Fatty acids of chain of a sarcomere that serves as the
villi Undulations and folds in a tissue length less than 2–6 carbons; also insertion site of actin thin filaments.
that serve to increase surface area; known as short chain fatty acids. zona pellucida A thickened
most commonly seen in the voltage-gated ion channel A glycoprotein extracellular matrix of a
gastrointestinal tract. membrane protein containing an mammalian ovum; it binds the sperm
viscosity An internal property of a fluid aqueous pore that can be opened in to initiate the acrosomal reaction.
that results in resistance to flow. response to changes in the zwitterion A molecule with groups that
Thick liquids have high viscosity. membrane potential. can become positive and others that
viscous effects The antagonism to vomeronasal organ A vertebrate sense can become negative.
movement of an object due to the organ adjacent to the mouth and zygote The single cell arising from the
interaction of its surface with the nasal cavities that is involved in fertilization of an ovum by a sperm.
fluid through which it moves. detecting pheromones.

Introduction to Physiological Principles
Physiological research exploded in the 1960s as a result of teams of researchers collaborate as multidisciplinary
several related events. Advances in diverse technologies, teams, exploring projects that would otherwise be prohibi-
from nuclear medicine to molecular genetics, paved the tative. The ease of travel and growth of the worldwide re-
way for new approaches to studying animal diversity. Pop- search community created opportunities for physiologists
ulation demographics led to massive hiring of university- to study unusual animals in exotic places.
based scientists, creating a critical mass of researchers It was during this period that Dr. Per Scholander, a
interested in understanding the physiological diversity of renowned animal physiologist and director of the Scripps In-
animals. It became commonplace to see international stitute of Oceanography (University of California, San Diego),

From Chapter 1 of Principles of Animal Physiology, Second Edition. Christopher D. Moyes, Patricia M. Schulte.
Copyright © 2008 by Pearson Education, Inc. Published by Pearson Benjamin Cummings. All rights reserved.
Introduction to Physiological Principles

Research vessel, Alpha Helix.

spearheaded an initative that would allow teams of interna-

tional researchers to work together to study biological prob-
lems in remote locations. After many years of effort and
negotiation with researchers, universities, and government
agencies, the Alpha Helix program was launched.
The Alpha Helix was an oceanic research vessel named
after the structural model of DNA proposed by Watson and
Crick only 10 years earlier. It was purchased in 1964 by the
Scripps Institute of Oceanography through a $1.5 million Elephant seal.
grant from the U.S. National Science Foundation. The ship
was built to provide technically sophisticated laboratories The trip home passed through the Galapagos Islands,
for experimental biologists to use as the ship explored the where researchers studied the same animals that Darwin
unusual natural habitats of the world. Although launched studied a century earlier. The cruises over the next 15 years
and funded by the U.S. government, it supported the re- took researchers back to these same locations, and to oth-
search of both American and international scientists. On ers such as the Bering Sea (cold-water fishes), New Guinea
her maiden voyage in 1966, the Alpha Helix carried 12 crew (tropical animals), Guadalupe Island (fish and elephant
members and 10 scientists around the world on a “quest of seals), Antarctica (polar animals), the eastern Pacific (reef
biological and medical knowledge.” The Alpha Helix pro- animals, sharks, whales), Australia (sea snakes), Hawaii
gram was a career-changing experience that inspired a (deep-sea fishes), and the Philippines (nautilus). Many of
whole generation of animal physiologists. these animals had never been studied, and their physiolog-
The ship was the floating laboratory for three or four ical properties were largely mysterious at that time.
expeditions each year, bringing together teams of scien- The Alpha Helix exemplified the explosion of work in
tists with complementary interests and expertise. The inau- animal physiology that began in the 1960s. The Alpha Helix
gural expedition of the Alpha Helix was a six-month program continued until 1980, at which point government
expedition to the Great Barrier Reef, where researchers support ended and the ownership of the vessel was trans-
studied coral reefs, tropical mangrove forests, and the ani- ferred to the National Science Foundation. The vessel itself
mals that lived in the sea and on land. Three months after remains in active duty, based at the University of Alaska, and
returning from Australian waters, a new expedition was is used for international oceanographic research. The Alpha
launched to South America. The Alpha Helix traveled up the Helix program gave hundreds of researchers the opportunity
Amazon River to study the behavioral and evolutionary to learn firsthand about the diversity of the natural world and
properties of fish and terrestrial animals in the neotropics. how organisms function in their various environments.2

Introduction to Physiological Principles

In the words of the renowned Genotype Evolution
physiologist Knut Schmidt-
Nielsen, animal physiology is Adult Phenotype
“the study of how animals
work.” Animal physiologists
study the structure and function Cells
of the various parts of an ani-
mal, and how these parts work Development Tissues Physiology Reproduction
together to allow animals to behavior
perform their normal behaviors Organs
and to respond to their environ-
ments. One hallmark of animal systems
physiology is diversity. More
than a million different species
of animals live on Earth, each Environment Random Natural
processes selection
of which has acquired through
evolution countless unique
properties. Each physiological
process is a product of the activ-
ities of complex tissues, organs, Figure 1 An overview of the factors influencing the phenotype of
adult animals
and systems that can arise
through complex patterns of genetic regulation of influence the adult phenotype. Organisms may
countless cells. change their behavior as a result of learning, or al-
Despite this great diversity, there are many ter their physiological responses through modifica-
commonalities within physiology—unifying themes tion of their phenotypes. Ultimately, the phenotype
that apply to all physiological processes. First of all, (morphology, physiology, and behavior) of an ani-
physiological processes obey physical and chemical mal influences its reproductive success. Differential
laws. Second, physiological processes are regulated survival of organisms with distinct phenotypes may
to maintain internal conditions within acceptable result in evolutionary change in the genotype of a
ranges. This internal constancy, known as homeo- population over many generations.
stasis, is maintained though feedback loops that
sense conditions and trigger an appropriate re-
sponse. Third, the physiological state of an animal Physiology: Past and Present
is part of its phenotype, which arises as the product
of the genetic makeup, or genotype, and its inter- Modern animal physiology is a discipline con-
action with the environment. Fourth, the genotype cerned with the whole range of processes that af-
is a product of evolutionary change in a group fect animal function. Although animal physiology
of organisms—populations or species—over many is an experimental science that can trace its roots
generations. back more than two millennia to the ancient
Most physiological studies examine how vari- Greeks, it plays an important role in modern biol-
ous processes affect the physiological phenotype of ogy as the intellectual glue that holds disparate bi-
an animal (Figure 1). Both the genotype of an or- ological fields together.
ganism and its environment interact through devel-
opment to produce the phenotype of the adult
organism. The phenotype is itself the product of
processes at many levels of biological organization, A Brief History of Animal Physiology
including the biochemical, cellular, tissue, organ, Although Greek thinkers such as Hippocrates
and organ system levels. Together these processes (460–circa 377 B.C., the father of medicine) and
interact to produce complex behaviors and physio- Aristotle (384–322 B.C., the father of natural his-
logical responses. The environment can, in turn, tory) were not primarily experimental physiolo-

Introduction to Physiological Principles

gists, Hippocrates’ emphasis on the importance of William Harvey (1578–1657) identified the
careful observation in the treatment of disease and path of blood through the body, and showed that
Aristotle’s emphasis on the relationship between contractions of the heart power this movement.
structure and function make them important fig- Although Harvey could not see the fine capillaries
ures in the history of physiology. Claudius Galenus that connect arteries and veins using the crude
(A.D. 129–circa 199), known as Galen, was the first magnifying glasses that were available at the
to use systematic and carefully designed experi- time, he postulated that they must exist to form a
ments to probe the function of the body. Galen closed circulation for the blood around the body.
made extensive use of dissection and vivisection of Harvey showed how dissections, close observa-
nonhuman primates such as Barbary apes and tion of living organisms, and careful experiments
other mammals to test his physiological ideas. For could be combined to teach us about the func-
example, Galen performed experiments in which tions of the body.
he tied off the ureters (the tubes leading from the Prior to the 18th century, physiologists fell into
kidney to the bladder), and observed that the kid- one of two camps. The iatrochemists believed that
neys swelled. From this observation he concluded body function involved only chemical reactions,
that the kidneys play a role in the formation of whereas iatrophysicists believed that only physi-
urine. Similarly, he tied off the laryngeal nerve cal processes were involved. In the late 17th and
(which leads to the vocal cords) of a living pig, at early 18th centuries a Dutch physician, Hermann
which point the pig stopped squealing. From this Boerhaave, and his Swiss pupil, Albrecht von
experiment, he concluded that the brain and nerves Haller, proposed that bodily functions were a com-
regulate the voice. This experimental work, com- bination of both chemical and physical processes.
bined with his practice as a physician to the Roman By uniting these two approaches, these researchers
gladiators, allowed him to formulate detailed de- were among the earliest proponents of physiology
scriptions of anatomy and elucidate the basis of as we understand it today.
many physiological processes. Although much of In the 19th century physiological knowledge
Galen’s work was fundamentally incorrect when began to accumulate at a rapid rate. For example,
viewed from a modern perspective, his emphasis in 1838 Matthias Schleiden and Theodor Schwann
on careful observation and experimentation makes formulated the “cell theory,” which states that or-
him the founder of physiology. ganisms are made up of units called cells, a discov-
During the Middle Ages the medical traditions ery that paved the way for modern physiology.
of the ancient Greeks were practiced and further Claude Bernard (1813–1878) discovered that he-
developed by physicians in the Muslim world, moglobin carries oxygen, that the liver contains
most notably Ibn al-Nafis (1213–1288), who was glycogen, that nerves can regulate blood flow, and
the first to correctly describe the anatomy of the that ductless glands produce internal secretions
heart, the coronary circulation, the structure of (hormones) that are carried in the blood and influ-
the lungs, and the pulmonary circulation. He was ence distant tissues. One of Bernard’s most impor-
also the first to describe the relationship between tant contributions was his concept of the milieu
the lungs and the aeration of the blood. interieur (internal environment); he postulated
The Renaissance brought a new flowering of that living organisms preserve a distinct internal
physiological research in the Western world. Jean- environment despite changes in the external envi-
Francois Fernal (1497–1558) outlined the current ronment. This concept—the ability to maintain a
state of knowledge of human health and disease. constant internal environment—was later devel-
Andreas Vesalius (1514–1564), author of the first oped more fully by the American physiologist Wal-
modern anatomy textbook, demonstrated that ter B. Cannon (1871–1945), who coined the term
Galen had made many errors in both anatomy and homeostasis.
physiology. Because Galen was thought to have Until the 20th century, physiologists made lit-
done everything that was necessary to understand tle distinction between animal physiology and
the workings of the body, many medical practi- medical physiology. Most physiological experi-
tioners of the time shunned physiological re- ments on animals were performed with the goal of
search. Thus, by showing that Galen was not improving the understanding of the human body
entirely correct, Vesalius’s work triggered the both in health and in illness. But in the 20th cen-
modern study of anatomy and physiology. tury biologists became interested in applying the

Introduction to Physiological Principles

newly emerging physiological knowledge to ani- Any attempt to survey the major figures in the
mals living in diverse environments, and in trying history of animal physiology excludes countless
to understand the nature of physiological diversity. other researchers who have made important con-
Per Scholander (1905–1980) was one of the tributions to the field.
first and most influential of these comparative
physiologists. Scholander studied a remarkable
diversity of physiological responses, including the
mechanisms involved in diving vertebrates, the re- Subdisciplines in Physiological
sponses of warm-blooded animals to cold environ- Research
ments, and how fish fill their swim bladders Modern physiological knowledge is the product of
(air-filled organs that fish use for buoyancy). the efforts of multitudes of scientists with diverse
Scholander also organized the influential expedi- interests and expertise. Typically, an animal phys-
tions of the Alpha Helix in the research program iologist specializes in one or two subdisciplines of
described in the opening essay of this chapter. physiology, with an awareness of the central is-
The contributions of C. Ladd Prosser sues in other, related subdisciplines. There are
(1907–2002) include the discovery of so-called three main ways to categorize physiological sub-
central pattern generators. These groups of disciplines: by the biological level of organization,
neurons coordinate many rhythmic behaviors, in- by the nature of the process that causes physio-
cluding breathing and walking. Prosser also dis- logical variation, and by the ultimate goals of the
covered the relationship between muscle diameter research.
and conduction speed, and during World War II he
worked on the effects of radiation on animal life as
part of the Manhattan Project. Physiological subdisciplines can be
Knut Schmidt-Nielsen (1915–2007) devoted his distinguished by the biological level
career to understanding how animals live in harsh of organization
and unusual environments. In his classic early work Since physiology is concerned with biological func-
on the adaptations of the camel to desert life, he tion at many levels of organization (Figure 2), one
showed that the camel’s nose contains a countercur- of the most common ways to distinguish branches
rent exchanger that allows it to recapture moisture of physiology is by reference to these levels.
from exhaled air, resulting in an almost 60% reduc-
tion in water loss compared to other mammals. • Cell and molecular physiologists study
George Bartholomew (1923–2006) is the founder phenomena that occur at the cellular level,
of the field of ecological physiology, or the study of although these effects have important con-
how an organism interacts with its environment. sequences for higher levels of organiza-
Bartholomew combined the study of animal behav- tion. Cell and molecular physiologists
ior, ecology, and physiology to assess the evolution- might include researchers studying molec-
ary significance of adjustments or adaptations in ular genetics, signal transduction, meta-
animals to their environments. He identified the in- bolic biochemistry, or membrane biophysics.
dividual as the principal unit of natural selection, • Many physiologists focus their efforts on
and emphasized the importance of variation in specific physiological systems. A systems
physiology. physiologist is concerned with how cells
Peter Hochachka (1937–2002) and George and tissues interact to carry out specific re-
Somero (1941–) founded the field of adaptational sponsibilities within the whole animal. In
biochemistry. By applying the concepts and tech- fact, each of the chapters in Part Two of this
niques of biochemistry to the questions of compar- text is focused on a physiological system.
ative physiology, they have extended to the Thus, there are respiratory physiologists,
subcellular level our understanding of how ani- sensory physiologists, and so on.
mals adapt to hostile environments, providing in- • An organismal physiologist is most often
sights into the biochemical mechanisms that allow concerned with the way an intact animal un-
animals to live in habitats as diverse as the deep
sea, the Antarctic oceans, high mountain peaks,
and tropical rain forests.

Introduction to Physiological Principles


Organ systems


Populations Cells



Communities Ecosystems Biosphere

Figure 2 Levels of biological organization Chemists and biochemists study the

properties of atoms and molecules. Molecular biologists study the properties of molecules and
cells. Physiologists study the interactions between molecules, cells, tissues, organs, and organ
systems to understand the structure and function of an organism. Ecologists study the interactions
of organisms, populations and communities to understand the properties of ecosystems, and
ultimately the biosphere.

dertakes a specific process or behavior. For An organismal characteristic such as meta-

example, an organismal physiologist might bolic rate is the product of multiple physio-
study changes in animal metabolic rate in logical systems interacting in complex ways.
response to a stressor, such as temperature. Some organismal physiologists specialize in

Introduction to Physiological Principles

particular groups of animals: thus, there are Physiological subdisciplines can be

marine mammal physiologists, avian physi- distinguished by the process that
ologists, fish physiologists, and so on. generates variation
• An ecological physiologist studies how the Many physiologists are interested in how biologi-
physiological properties of an animal influ- cal functions change over time or in response to
ence the distribution and abundance of a changes in the environment. Thus, physiology can
species or population. For example, an eco- also be divided on the basis of the mechanism by
logical physiologist may study how the nutri- which changes or differences in physiological
ent distribution in the environment influences processes arise.
the growth rate of an animal. While organis-
mal physiologists may focus their research on • A developmental physiologist studies how
an interesting group of animals, ecological structures and functions change as animals
physiologists are more concerned with how grow through the various life stages from
an interesting environment affects diverse embryo to reproductive maturity, to senes-
animals within that environment. cence and death. These developmental path-
ways transform omnipotent stem cells into
• An integrative physiologist attempts to un-
specialized cells, forming multicellular tis-
derstand physiological processes at a vari-
sues and physiological systems. To under-
ety of levels of biological organization and
stand the diversity in animal morphology
across multiple physiological systems. For
and function, it is important to appreciate
example, an integrative physiologist might
how these structures arise in development.
study how variation in hemoglobin genes
contributes to differences in oxygen deliv- • An environmental physiologist assesses how
ery and how those differences in the ability animals mount physiological responses to
to extract oxygen from the environment environmental challenges. For example,
contribute to the geographical distribution changes in temperature have the potential to
of the species. affect many physiological systems in complex
ways. An environmental physiologist is con-
Of course, there is a great deal of overlap among
cerned with the way an individual animal or-
these subdisciplines, and making distinctions
ganizes or reorganizes its physiology to
among them is often difficult. In fact, few physiolog-
survive the environmental challenge.
ical researchers confine themselves exclusively to
investigating a single level of biological organiza- • An evolutionary physiologist is primarily
tion. Often a physiologist interested in a process at concerned with explaining how specific
one level of organization also studies its function at physiological traits arise within lineages
the next lower level. This approach, known as re- over the course of multiple generations.
ductionism, assumes that we can learn about a sys- Thus, evolutionary physiologists may be in-
tem by studying the function of its parts. Although a terested in the origins of variation within
reductionist approach can be extremely illuminat- populations of a single species, or the basis
ing, and has been the basis of many important bio- of differences between closely related
logical discoveries, ultimately many processes have groups of animals.
characteristics that are not apparent simply by ex-
amining the component parts. This feature of com-
plex systems is called emergence, which is just
Animal physiology can be a pure or an
another way of saying that the whole is often more
applied science
than the sum of its parts. The emergent properties Physiological research can be distinguished on the
of a system are due to the interactions of the com- basis of the ultimate goal. The research of an
ponent parts of the system, and can be difficult to applied physiologist is intended to achieve a spe-
predict by studying each part in isolation. Physiolo- cific, practical goal. For example, physiologists
gists are usually interested in these emergent prop- study some animals because of their economic im-
erties, and thus physiologists study how molecules, portance. Thus, veterinary medicine relies on
cells, and tissues interact to produce the complex physiological research to improve the health of
system that is an organism. agricultural animals and household pets. Simi-

Introduction to Physiological Principles


August Krogh Models in Animal Physiology

A model species is an organism that is proteins. Xenopus oocytes are large, so scientists can
studied by a wide community of researchers be- easily introduce foreign RNA by microinjection. The RNA
cause (1) it has features that are conducive to experi- is then translated and the protein sent to the appropri-
mentation and (2) understanding a process in the model ate location. For example, microinjection of RNA coding
provides insight into how the process works in other for membrane proteins causes the oocyte to translate
species of interest. Each model species has been cho- the protein and insert it into the membrane where its
sen because it demonstrates a combination of features functional properties can be assessed.
that make it well suited to some studies, though not all Many animals are useful models because of their de-
studies. This approach of using an animal model with velopmental biology. Nematodes are small animals
features that are favorable for scientific study is known composed of only a few thousand cells. The development
as the August Krogh principle: For every biological prob- from fertilized egg to adult has been studied to the point
lem there is an organism on which it can be most conve- that the fate of each cell has been mapped. Researchers
niently studied. can microinject substances into a designated cell at a
The importance of specific model systems changes specific developmental stage, knowing that specific cell
over time, as technologies advance and genomic data- will divide and differentiate into a specific tissue or or-
bases expand. An animal that was inconvenient to study gan. Zebra fish are useful models because the embryo
in the past may be much easier to study now. For exam- grows quickly and remains transparent for much of its
ple, mice became more useful models in developmental early development. This allows researchers to follow
physiology when transgenic mouse technologies be- complex cellular changes in living animals. Such studies
came readily available. are aided by transfection of genes encoding fluorescent
Knowledge gained from model systems is useful only if proteins that can be monitored more easily.
that information is relevant to other species. Most com- One important factor that determines the utility of a
monly, a model was originally chosen because of parallels model species is the ease with which genes can be
with human biology. Although the major model animals modified. The ability to generate mutations that result in
are quite different in appearance, much of the genetic and the gain or loss of a function allows physiologists to ex-
structural machinery that underlies development is simi- plore the importance of structural features. For many
lar among animals. The early patterns of embryonic de- years, random mutagenesis was the only way to gener-
velopment are similar in most vertebrate models, such as ate mutants. During this period, invertebrates and
zebra fish, chickens, mice, and humans. However, there small fish were used because it was possible to conduct
are always concerns about the phylogenetic distance be- large-scale screening projects to identify interesting
tween model systems. For this reason, each taxon has one mutants. More recently, genetic approaches to physiol-
or more species that have been trumpeted as a model. ogy have been facilitated by two trends. First, the prolif-
Some animals are useful models because they have eration of techniques for targeted mutagenesis makes it
unusual anatomical features. Perhaps the most famous easier to work on animals with long generation times,
example of such a model system is the squid giant axon. because large-scale screening is not needed. Second,
Squid are relatively simple animals that have certain ax- there is a rapid growth in the number of species for
ons large enough to be easily seen and readily manipu- which we have genomic information. Models become a
lated. The oocytes of the African clawed frog (Xenopus lot more convenient to use in genetic studies when we
laevis) are useful as models for the expression of foreign know their entire genome.

larly, much physiological research is aimed at un- In contrast to a medical physiologist, who uses
derstanding the human body. Although the ulti- animals to understand the human condition, a
mate goal of medical physiology is to understand comparative physiologist studies animals to ex-
human disease, medical physiology relies on other plore the origins and nature of physiological diver-
species as model systems (see Box 1, Methods and sity. Comparative animal physiology thrives on the
Model Systems: August Krogh Models in Animal breadth of physiological diversity, all the while
Physiology). searching for unifying themes.

Introduction to Physiological Principles

cules, or solubility of gases in solution. Physiologists

often borrow concepts and techniques from the
1. How would you define physiology? physical and chemical sciences, including engi-
2. Who were some of the major figures in neering, to help them understand how animals
physiology prior to the 20th century? work.
3. How do 20th-century comparative physiologists
differ from earlier physiologists?
4. What are the subdisciplines of physiology?
Mechanical theory helps us understand
how organisms work
5. How do some of the other sciences help us to
understand physiological processes? Each material has physical properties that are
useful in some contexts but not others. It would be
a mistake for an engineer to design a skyscraper
from Styrofoam, or a kite of concrete. Likewise, bi-
Unifying Themes in Physiology ological materials, or biomaterials—proteins, car-
In spite of the vast and diverse nature of animal bohydrates, and lipids—also have characteristic
physiology, several unifying themes and princi- physical properties that make them useful for
ples apply to all of its subdisciplines (Table 1). some processes but not others. For example, some
proteins are rigid and inflexible whereas others
readily deform. The physicochemical characteris-
tics of these biomaterials are determined by their
Physics and Chemistry: The Basis molecular properties. For example, a network of
of Physiology proteins can be made more rigid by additional
To understand physiology you need a basic under- bonds that cross-link proteins together. Cells use
standing of chemistry and physics. Animals are enzymatic reactions to fine-tune the physical
constructed from natural materials and thus obey properties of macromolecules. The macromole-
the same physical and chemical laws that apply to cules combine to form cells, which are collected to-
everything that we see around us. Temperature, gether to form tissues. Thus, the mechanical
for example, exerts its effects on physiology by al- properties of a tissue, such as bone, are conferred
tering the nature of chemical bonds in biomole-

Table 1 Unifying themes in animal physiology.

Unifying theme Examples

Physiological processes Mechanical engineering rules apply to physical properties of animals.
obey the laws of physics Chemical laws, including the effects of temperature, govern interactions between
and chemistry. biological molecules.
Electrical laws describe membrane function of all cells, including excitable cells.
Body size affects many physiological processes.
Physiological processes Homeostasis is the maintenance of internal constancy.
are usually regulated. Negative feedback loops help maintain homeostasis.
Positive feedback loops generate an explosive response.
The physiological Even identical genotypes can result in different phenotypes.
phenotype is a product Phenotype changes with normal development.
of the genotype and the Phenotype changes with environmental and physiological challenges.
environment. Phenotypic plasticity is the ability of a phenotype to change in response to environmental
A genotype is the product The definition of adaptation is context dependent.
of evolution, acting In the strictest evolutionary sense, adaptation refers to a trait that confers an increase
through natural selection in reproductive success.
and other evolutionary Adaptation can also refer to phenotypic changes that improve the performance of a
processes. physiological system, without underlying evolutionary change.
Not all physiological differences are adaptations.

Introduction to Physiological Principles

by the molecular properties of the components of the produced by tissue metabolism, and thus the meta-
bone-forming cells, the nature of the connections be- bolic rate of the animal as a whole depends on the
tween cells, and the interactions between tissues. mass of tissues. Metabolic heat is lost across the sur-
In addition to mechanical properties, other en- face of the body. Since heat production varies with
gineering concepts such as flow, pressure, resis- body mass and heat loss varies with body surface
tance, stress, and strain play important roles in area, a larger animal has more difficulty shedding
physiology. An engineer designing a system to metabolic heat than does a smaller animal.
pump water from a deep well takes into consider- It has long been known that metabolic rate of
ation factors such as the pressure gradients, fluid animals does not increase proportionately with
dynamics, the power of the pump, and resistance body mass. That is, animals differing 10-fold in
in the plumbing. A cardiovascular physiologist has body size differ less than 10-fold in metabolic rate
the same concerns in trying to understand how the (Figure 3). In the late 1800s, Max Rubner reported
heart delivers blood through the blood vessels. that the metabolic rate of dogs of various sizes was
constant when body surface area was taken into
account. For many years, it was thought that the
Electrical potentials are a fundamental relationship between body mass and metabolic
physiological currency rate was related to the ratio of surface area to vol-
Just as we use electricity to power many of the ma- ume. In the 1930s, Max Kleiber examined the in-
chines we use in our daily lives, animals use elec- fluence of body size on metabolic rate of birds and
tricity to power cellular activities. Cells establish a mammals. Based on these data, he formulated the
charge difference across biological membranes by allometric scaling equation, relating body mass
moving ions and molecules to create ion and elec- (M) and metabolic rate (y)
trical gradients. All cells and many organelles y ⫽ aM b
within cells rely on this potential difference, or
membrane potential, to drive processes that are where a is the normalization coefficient and b the
needed for survival. Animals also use changes in scaling coefficient. Kleiber’s work suggested the
electrical potentials to send signals within and be- value for b was closer to 0.75 (3/4) rather than the
tween cells, helping to coordinate the complex value of 0.67 (2/3) expected from Rubner’s studies.
processes of the body. Muscles and neurons, two These data, and many studies since, suggest that al-
cell types that are found only in animals, use lometric scaling of metabolism is not easily ex-
changes in membrane potential to send signals. plained by simple differences in ratio of surface
Thus, electrical theory has played an important area to volume. Despite the complexity of size-
role in helping physiologists to understand the dependent physiological properties, or perhaps
way that neurons and muscles work.

Biochemical and physiological patterns 1000 Elephant

Metabolic rate (watts)

Line of
are influenced by body size 100
unity Horse

From tiny zooplankton weighing less than a mil- Chimpanzee
ligram to blue whales weighing over 100,000 kg, Goose
animals vary greatly in body size, and these dif- 1
ferences have profound effects on physiological
processes. One reason is that the ratio of the surface Small birds
area to volume changes with body size. Consider an
animal shaped like a sphere. With a radius r, its 0.01 0.1 1 10 100 1000 10,000
Body mass (kg)
mass, or rather its volume (V) ⫽ (4/3)πr3 and its sur-
face area (A) ⫽ 4πr2. Since surface area increases by Figure 3 Metabolic rate of various birds and
the power of two, and volume increases by the mammals plotted against body weight on a double
power of three, the surface area is proportional to logarithmic scale The line of unity shows the relationship
that would be expected in the absence of allometric scaling. In
the volume to the 2/3 power, or V 0.67. This relation- this figure, an animal that is 10 times larger than another has a
ship between surface area and volume has an im- metabolic rate that is only about 7 times greater.
portant influence on thermal biology. Heat is (Source: Adapted from Schmidt-Nielsen, 1984)

Introduction to Physiological Principles

because of the complexity, allometric scaling re- regulate a particular variable. For example, your
mains one of the dominant themes in comparative body temperature remains relatively constant only
animal physiology. Normally reticent physiologists because numerous physiological processes actively
have been inspired to engage in animated, and change, adjusting the rates of heat production and
sometimes vitriolic arguments about both the exact heat loss. For example, when you stand in the cold
value of b and the underlying mechanisms. air, your muscles may shiver to produce heat that
replaces the heat lost to the environment. Thus,
muscle activity changes in order to maintain con-
stant body temperature.
Physiological Regulation The nature of the physiological response to an
Most organisms are faced with environmental vari- environmental change depends on many factors.
ation. Temperature, food availability, and the phys- Short-term challenges can often be dealt with us-
iochemical environment around an animal may ing existing physiological systems. When a dog is
change with the time of day, the season, or the move- too hot, it can move to a cooler location or pant to
ment of an animal across the landscape. Multicel- shed heat in its breath. These are effective short-
lular animals can be classified according to the term behavioral and physiological approaches to
strategies they use to cope with changing conditions. reducing thermal stress. However, they are not ef-
Conformers allow internal conditions to fective long-term strategies. A dog hiding in the
change when faced with variation in external con- shade cannot hunt for food, and panting conflicts
ditions. For example, the body temperature of a fish with oxygen delivery during running. Instead,
will be low in cold water and high in warm water. dogs cope with long-term changes in temperature,
Thus, each of the cells in a fish’s body must cope such as seasonal cycles, by growing fur in the au-
with the effects of changes in external temperature. tumn and shedding fur in the spring.
Regulators maintain relatively constant in- This example illustrates several principles that
ternal conditions regardless of the conditions in govern physiological changes. First, some physio-
the external environment. Your body temperature logical strategies are effective in the short term but
is likely to be approximately 37°C whether you are less useful for the long term. Holding your breath
in a warm room or standing outside on a very cold may be fine for diving to the bottom of a lake, but
day. Your body has mechanisms to maintain its in- it will not help you cope with low oxygen levels
ternal temperature, and thus the vast majority of while you climb Mount Everest. Second, some
the cells in your body do not have to cope with the strategies require a significant investment in re-
effects of changes in ambient temperature. sources and need longer to take effect. Hair
Each strategy has its benefits and costs. Be- growth, for instance, is a relatively slow process
cause physiological responses demand metabolic that requires metabolic energy. Third, some stres-
energy, conforming is much less expensive than sors are sufficiently predictable that animals re-
regulating. However, environmental changes can model physiology in anticipation of the stress, and
have deleterious effects on physiology, so regulat- often in predictable cycles. Many physiological
ing provides a much more stable internal environ- processes change daily, showing a circadian
ment. Animals may be regulators with respect to rhythm. Some changes are seasonal, such as the
one internal parameter, but conformers with re- growth and shedding of fur. Other patterns, such as
spect to another parameter. For example, lizards human reproductive cycles, are linked to the lunar
conform to external temperature but regulate their cycle. In some cases, cyclical physiological changes
internal salt concentrations within a narrow range. proceed without any environmental input, but gen-
erally they arise in response to specific environ-
mental cues, such as temperature or photoperiod.
Homeostasis is the maintenance
of internal constancy
The maintenance of internal conditions in the face
Feedback loops control
of environmental perturbations is referred to as
physiological pathways
homeostasis. The word homeostasis does not im- To maintain homeostasis, animals must (1) de-
ply that there is no change in the organism, only that tect external conditions and (2) if necessary ini-
the animal initiates specific responses to control or tiate compensatory responses that (3) keep vital

Introduction to Physiological Principles

areas buffered against unfa-

+ Heat production –
vorable change. Animals most
often maintain homeostasis
Cold Hot
using a reflex control path- Reduced exposure Normal exposure Elevated
way. A change in the inter- Tb Tb Tb
nal or external environment
provides a stimulus. The
stimulus then causes a re- – Heat dissipation +
sponse. For instance, when
you depress the gas pedal of Figure 4 Antagonistic controls Your body temperature is held relatively constant by
your car (the stimulus), the antagonistic loops. If cold conditions cause a decrease in your body temperature, this triggers
an increase in heat production and a reduction in heat dissipation. When body temperature
car accelerates (the re- increases, heat production pathways are inhibited and heat dissipation pathways are
sponse). If you take your foot stimulated, correcting body temperature.
off the gas (remove the stim-
ulus), the car will slow down.
Animals fine-tune physiological responses by Positive feedback loops cause
using antagonistic controls: independent regu- explosive responses
lators that exert opposite effects on a step or path-
Some physiological systems are controlled by
way. In the car analogy above, the gas pedal and
positive feedback loops. Unlike negative feed-
the brake are examples of antagonistic controls.
back, which minimizes changes in the regulated
You can cause the car to decelerate by taking your
variable, positive feedback loops maximize changes
foot off the gas or depressing the brake, but the
in the regulated variable. For example, the mus-
car’s response will be greater if you use both in
cles in the stomach are normally regulated to con-
combination. Animals control body temperature
tract and relax in a regular pattern to gently mix
by regulating both heat production and heat dissi-
food. However, when a toxin is detected, a positive
pation (Figure 4). Hormones mediate many antag-
feedback loop is triggered to induce forceful con-
onistic controls. Insulin and glucagon are
tractions that propel the food back up the esopha-
antagonistic controllers of glucose levels.
gus to induce vomiting. Pathways involving
positive feedback loops begin slowly but rapidly
Negative feedback loops increase in intensity. In a positive feedback loop
maintain homeostasis there must also be a signal that allows the animal
to stop the process at the proper time, so that the
In a negative feedback loop, the response
action does not spiral out of control.
sends a signal back to the stimulus, reducing the
intensity of the stimulus. For example, when you
eat, the incoming food causes the stomach to
swell. The change in stomach volume and early Phenotype, Genotype,
digestion products trigger a negative feedback and the Environment
loop, acting through your brain, to reduce your The physiological properties of an animal are as-
appetite. pects of the animal’s phenotype. Physiological
Many physiological systems have a set-point, traits, like other characteristics of animals, are de-
a preferred physiological state defended through termined in large part by the genes of the
feedback loops. Your body temperature has a set- genome—the genotype—but are also influenced
point of approximately 37°C. When temperature by the way the genes are regulated, particularly in
rises, your body may sweat to cool you down, response to external conditions.
whereas a decrease in body temperature may trig- An individual genotype has the capacity to
ger shivering to warm you back to your set-point. produce considerable variation in cellular proper-
Although the set-point for human body tempera- ties. Although the same genes are found in each
ture is near 37°C, the exact body temperature set- cell, they are regulated in combinations to allow
point varies between individuals and changes animals to develop distinct tissues. During this
throughout the day. process of tissue formation, called morphogenesis,
networks of genes are turned on and off in precise

Introduction to Physiological Principles

patterns to create the appropriate phenotype. For

example, when the fertilized egg of a frog develops
into a tadpole, a developmental program is turned
on to produce the gills and a tail. When the tadpole
undergoes metamorphosis, another program is
triggered that results in the formation of the lungs
and legs, and death of the cells in the gills and tail.
In addition to orchestrating the normal develop-
mental program, the genotype controls the way
animals can alter their phenotype in response to
physiological and environmental conditions. For
example, changes in the expression of genes allow
your muscles to change in size and strength in re-
lation to exercise training. The differences in
genotype among animals are central to the pheno-
typic variation upon which natural selection acts.
Every individual genotype has a capacity to differ
in complex, often unpredictable ways because of (a) Daphnia reared (b) Daphnia reared
the way the genes respond to external conditions. in the absence in the presence
of predator extract of predator extract

Figure 5 Phenotypic plasticity and

A single genotype results in more than polyphenism Alternative morphs of the water flea,
one phenotype Daphnia pulex. When genetically identical individuals are
reared in the absence of predator extracts, these features
A single genotype can result in multiple pheno- are absent. When reared in the presence of chemical
types, depending on the environmental conditions extracts of predators, Daphnia pulex have a large helmet-
that the animal experiences. For example, if iden- shaped head and a long spiky tail.
tical twins were raised in different places, it is pos-
sible that one twin might grow taller than the they develop with much smaller heads and a
other due to differences in diet. This ability of a shorter, less spiky tail (Figure 5). Adult water fleas
single genotype to generate more than one pheno- retain these morphologies even if the predator ex-
type, depending on environmental conditions, is tracts are removed from the water.
called phenotypic plasticity. We observe this
phenomenon most commonly at the population
level, where individuals with similar genotypes Acclimation and acclimatization result
can have different phenotypes depending on envi-
in reversible phenotypic changes
ronmental conditions. The term phenotypic plas- Most animals are able to remodel their physiolog-
ticity encompasses a wide range of changes in ical machinery in response to external conditions.
phenotype, some reversible and some irreversible. Physiologists use the related terms acclimation
Developmental plasticity, or polyphenism, is a and acclimatization when referring to processes
form of phenotypic plasticity in which develop- that cause reversible changes in the phenotype of
ment under different conditions results in alterna- an organism in response to an environmental
tive phenotypes in the adult organism that cannot change. The word acclimation refers to the
be reversed by subsequent changes in the environ- process of change in response to a controlled en-
ment. The similar concept of a reaction norm, or vironmental variable (usually in a laboratory set-
the range of phenotypes produced by a particular ting), while the word acclimatization refers to the
genotype in different environments, applies to process of change in response to natural environ-
phenotypes that exist as a continuum. For exam- mental variation. For example, if you take a fish
ple, when water fleas (Daphnia pulex) are reared from water at 15°C and leave it in water at 5°C,
in the presence of predators (or even chemical ex- you will observe a variety of changes in muscle
tracts of predators) they develop large, armored, biochemistry, metabolic rate, and other physiolog-
helmet-shaped heads and an elongated spiny tail. ical parameters. This process would be referred to
When they are reared in the absence of predators, as acclimation. In contrast, if you compare a fish

Introduction to Physiological Principles

that you capture in the summer from a lake with a ural selection, that is, a change in a population or
mean temperature of 15°C with a fish that you group of organisms over evolutionary time. Many
capture in winter from a lake at 5°C, you will ob- evolutionary biologists argue that the word
serve many of the same changes, but in this case adaptation should only be used in this context.
the process would be termed acclimatization. Ac- However, physiologists often use the word
climatization may be the result not just of the tem- adaptation as a synonym for the word acclimation.
perature change, but also of changes in day One usage is in the context of phenotypic plasticity:
length, food availability, and any other environ- a beneficial change in an individual’s physiology
mental parameters that vary between summer that occurs over the course of its lifetime. For exam-
and winter. In general, both acclimation and ac- ple, a medical physiologist might discuss exercise
climatization are reversible physiological changes. adaptations: the changes in the muscles and heart
that occur during exercise training. In this text,
adaptation is used in the context of evolutionary
adaptation, but it is important that you learn to
Physiology and Evolution make the distinction between this definition and
One of the fundamental challenges of animal phys- the way the term is used by other scientists and the
iology is to understand and account for the great general community.
diversity of animal body forms and the strategies To an evolutionary physiologist, an adaptation
that animals use to cope with their environments. is a trait that arose via a process such as natural
Consider the neck of a giraffe, which, in relation to selection and conveys an increase in reproductive
its body size, is far longer than the neck of its clos- success. Thus, an evolutionary adaptation is the
est living relative, the okapi. When a physiologist result of processes that occur over the course of
thinks about the neck of a giraffe, what question many generations, rather than within the lifetime
first springs to mind? A respiratory physiologist of a single individual. The evolution of insecticide
might wonder: how can a giraffe breathe through resistance in insects provides an excellent exam-
such a long neck? A cardiovascular physiologist ple of the principles of adaptive evolution. Over the
might wonder: how can a giraffe’s heart pump last 50 years, chemical insecticides have been
blood all the way up to its head? These mechanis- used to kill insects that harm crops or carry dis-
tic questions are amenable to the experimental ease. For instance, organophosphates have been
methods of physiology and can be addressed using used for decades to control populations of insects,
many of the techniques and conceptual ap- such as the common house mosquito Culex pipi-
proaches we discuss in this text. In contrast, an ens. Organophosphates kill mosquitoes by inhibit-
evolutionary physiologist might wonder: why does ing acetylcholinesterase, an enzyme that is vital
a giraffe have a long neck? This question actually for neuronal transmission. The insecticides kill off
encompasses two different kinds of thinking. If we all or most of the susceptible mosquitoes, but
wish to address the proximate cause of the gi- those few rare individuals with beneficial muta-
raffe’s long neck, we might examine the genes that tions survive and reproduce. This differential sur-
specify the size or number of vertebrae in the vival changes the structure of the population.
skeleton. Alternatively, we might wish to under- Resistant populations of Culex pipiens have
stand the ultimate cause of the giraffe’s long evolved in two ways. Some mosquitoes have mu-
neck: whether long necks provided an evolution- tations in the acetylcholinesterase gene, which
ary advantage to the ancestors of the giraffe. To makes the enzyme more tolerant of the insecticide.
address these ultimate questions we need to con- Other mosquitoes have extra copies of the esterase
sider the impact of evolutionary change and the gene, which encodes an enzyme that converts the
adaptive significance of the physiological traits organophosphate into a less toxic form. These mu-
that we study. tations are vital for survival in the presence of the
insecticide, but in the absence of insecticide the in-
dividuals carrying these mutations are at a disad-
What is adaptation? vantage. Those that overproduce esterase use
Adaptation has two distinct meanings within the energy that could serve other physiological func-
context of physiology. The most common usage tions; those with the mutated acetylcholinesterase
refers to the product or process of evolution by nat- have an enzyme that does not function quite as

Introduction to Physiological Principles

well as the nonmutant (or wild type). Thus, these diversity. One of the best ways to understand
genotypes are superior to wild-type genotypes how an animal works is to establish in which
only when the insecticides are present. ways the animal is similar to other organisms.
We can distill several general principles about Some animal traits are shared among all organ-
the process of evolutionary adaptation from the isms, some among all animals, and some among
evolution of insecticide tolerance in mosquitoes: related animals (lineages). Other traits are truly
unique to the species under study.
1. For evolution to occur, there must be varia-
When a new species of insect is discovered
tion among individuals in the trait under
deep in the heart of the Amazon jungle, we al-
ready know many of its features. Like all eukary-
2. The trait must be heritable—genetically deter- otic organisms, it will possess a genome of DNA,
mined and passed on to offspring. proteins of the same 20 amino acids, and phos-
3. The trait must increase fitness—the reproduc- pholipid membranes. Like other animals, its
tive success of the individuals that have the cells will be connected to each other with pro-
trait. teins such as collagen and elastin, and it will
4. The relative fitness of the different genotypes have nerves and muscles that allow it to sense
depends on the environment. If the environ- the world around it and move from place to
ment changes, the trait may no longer be place. Like other invertebrates, it will lack a
beneficial. spinal cord. Like other arthropods, it will have
an exoskeleton of chitin. Like other insects, it will
Not all differences are evolutionary have six legs and paired wings. We can be rea-
adaptations sonably certain of these features because the
new species of insect has an evolutionary history
Not all evolution is adaptive. For example, genetic
that included, at some point in the last billion
drift, or random changes in the frequency of par-
years, ancestors that it shared with other in-
ticular genotypes in a population over time, can
sects, invertebrates, metazoans, and ultimately
result in substantial differences in the phenotype
all eukaryotic organisms. Thus, species that are
of two populations, independent of any adaptive
closely related to each other are likely to share
evolution. Genetic drift is most likely to occur in
more common features than do species that are
small populations and is a result of happenstance,
distantly related.
not of differences in fitness. If a forest fire kills
most of the individuals of a population, the few
survivors may happen to display a different
genotype frequency than the ancestral popula- 2 C O N C EP T CH E CK
tion. After a number of generations, the derived 6. What are the major unifying themes in
population may differ from the ancestral popula- physiology?
tion, but not for any reason related to natural se- 7. What is homeostasis?
lection and fitness. This example of genetic drift is 8. Compare and contrast negative feedback with
known as the founder effect. positive feedback.
9. What is a phenotype?
Evolutionary relationships influence 10. What are some of the ways in which an
morphology and physiology individual’s phenotype can change?

Although it is easy to be overwhelmed by the di-

versity in animal form and function, animal biol-
ogists strive to understand the nature of this

Introduction to Physiological Principles

Physiology: Past and Present k Body size can have a profound influence on an-
k Throughout history, physiological advances imal physiology.
have been made because of detailed observa-
k Conformers allow their internal environment to
tions of living and dead animals, united with
change, whereas regulators maintain their in-
carefully planned experiments to elucidate how
ternal environment relatively constant in the
animals work.
face of external change.
k Advances in physiology have followed in step
k Homeostasis is the maintainance of an internal
with advances in physics, chemistry, and mo-
state that is constant or within tolerable limits.
lecular biology, which have allowed physiolo-
gists to gain an ever-increasing understanding k Homeostasis is maintained by reflex control
of animal structure and function. pathways that include antagonistic controls,
negative feedback, and positive feedback.
k Physiology can be divided into several subdisci-
plines. It can be divided based on the level of bi- k Negative feedback loops tend to minimize the
ological organization that the researcher change in the regulated variable, while positive
studies, what kind of physiological variation feedback loops tend to amplify the change.
the researcher studies, or the purpose of the
k An animal’s phenotype is the result of a com-
plex interaction between its genotype and its
k Physiological processes can be reduced to environment. Because of phenotypic plasticity,
their component parts at a lower level of bio- one genotype may produce many phenotypes,
logical organization and each part studied in depending on the effects of the environment.
isolation. Emergent properties of the system
k Polyphenism is a type of phenotypic plasticity in
result from the interactions of these parts and
which the environment that an organism en-
are not always evident when the parts are
counters as it develops influences the pheno-
studied in isolation.
type of the adult. These changes are usually
Unifying Themes in Physiology irreversible.
k A number of important unifying themes apply
k Acclimation and acclimatization are types of
across all of the subdisciplines of physiology.
phenotypic plasticity in which the environment
(1) Physiological processes obey physical and
causes reversible changes in an organism’s
chemical laws. (2) Physiological processes are
often regulated. (3) Genotype and phenotype
are linked. (4) Phenotypes are the product of k The genotype of an animal is the result of evo-
evolution. lutionary processes, including adaptation and
genetic drift.
k Physiological processes obey physical and
chemical laws, and physiologists often use the-
ories and ideas from physics, chemistry, bio-
chemistry, and molecular biology to help them
understand how organisms work.

Introduction to Physiological Principles

Synthesis Questions
1. Home heating systems such as a furnace are help the herpetologist understand the nature
regulated via negative feedback. Describe how of this variation.
such a system might work. 3. What physical, chemical, or physiological con-
2. A herpetologist (a biologist who studies rep- straints may lead to allometric scaling?
tiles and amphibians) brings two frogs into 4. Why do physiologists need to understand evo-
your lab. One frog is blue, and the other is lution?
green. For each of the main subdisciplines
5. Compare and contrast adaptive evolution and
that were described in this chapter, outline the
genetic drift.
kinds of investigations you might perform to

For Further Reading

See the Additional References section at the end This entertaining autobiography provides a
of the chapter for more references related to the personal glimpse into the life and work of one of
topics in this chapter. the 20th century’s greatest animal physiologists.
Physiology: Past and Present Schmidt-Nielsen, K. 1998. The camel’s nose:
Memoirs of a curious scientist. Washington,
The following four papers are essays on the DC: Island Press/ Shearwater Books.
history of important subdisciplines in physiology.
Each provides insight into the major questions Unifying Themes in Physiology
and suggestions for the future of the field.
The following works summarize some of the
Costa, D. P., and B. Sinervo. 2004. Field important unifying themes in animal physiology.
physiology: Physiological insights from
animals in nature. Annual Review of Feder, M. E., A. F. Bennett, W. W. Burggren, and
Physiology 66: 209–238. R. B. Huey. 1987. New directions in ecological
physiology. Cambridge: Cambridge University
Feder, M. E., A. F. Bennett, and R. B. Huey. 2000. Press.
Evolutionary physiology. Annual Review of
Ecology and Systematics 31: 315–341. Mangum, C. P., and P. W. Hochachka. 1998.
New directions in comparative physiology
Somero, G. N. 2000. Unity in diversity: A and biochemistry: Mechanisms, adaptations,
perspective on the methods, contributions, and and evolution. Physiological Zoology 71:
future of comparative physiology. Annual 471–484.
Review of Physiology 62: 927–937.
Tracy, C. R., and J. S. Turner. 1982. What is This fascinating book attempts to unify the
physiological ecology: A collection of disparate fields of developmental biology and
commentaries by noted physiological ecologists. evolution. It contains many important themes
Bulletin of the Ecological Society of America 63: that are relevant to animal physiology.
340–346. Gerhart, J., and M. Kirschners. 1997. Cells,
embryos and evolution: Toward a cellular
These two short books summarize the history of and developmental understanding of
medical physiology and some of the most phenotypic variation and evolutionary
important contributors to its development. adaptability. Malden, MA: Blackwell
Franklin, K. J. 1949. A short history of Science.
physiology. London: Staples Press.
Leake, C. D. 1956. Some founders of physiology.
Washington, DC: American Physiological

Introduction to Physiological Principles

This book of the collected essays of J. B. S. This brief review summarizes the mechanisms of
Haldane includes his famous essay on the insecticide resistance in mosquitoes.
problems of biological scaling. Raymond, M., C. Berticat, M. Weill, N. Pasteur, and
Haldane, J. B. S. 1985. On being the right size C. Chevillon. 2001. Insecticide resistance in the
and other essays, J. M. Smith, ed. Oxford: mosquito Culex pipiens: What have we learned
Oxford University Press. about adaptation? Genetica 112–113: 287–296.

These works address the concept of phenotypic This readable book discusses the physiological
plasticity from a variety of viewpoints. implications of animal size.
Piersma, T., and J. Drent. 2003. Phenotypic Schmidt-Nielsen, K. 1984. Scaling: Why is
flexibility and the evolution of organismal animal size so important? Cambridge:
design. Trends in Ecology and Evolution 18: Cambridge University Press.
Pigliucci, M. 2001. Phenotypic plasticity— This book provides a comprehensive introduction
Beyond nature and nurture. Baltimore: Johns to physics and engineering principles as applied
Hopkins University Press. to physiology.

West-Eberhard, M. J. 2003. Developmental Vogel, S. 1988. Life’s devices. Princeton, NJ:

plasticity and evolution. Oxford: Oxford Princeton University Press.
University Press.

Additional References
Alexander, R. M. 1985. The ideal and the feasible: Physical Gould, S. J., and E. S. Vrba. 1982. Exaptation: A missing term
constraints on evolution. Biological Journal of the Linnean in the science of form. Paleobiology
Society 26: 345–358. 8: 4–15.
Bartholomew, G. A. 1986. The role of natural history in Jorgensen, C. B. 1983. Ecological physiology: Background
contemporary biology. BioScience 36: 324–329. and perspectives. Comparative Biochemistry and
Bennett, A. F. 1997. Adaptation and the evolution of Physiology, Part A: Molecular and Integrative Physiology
physiological characters. In Handbook of physiology: A 75: 5–7.
critical, comprehensive presentation of physiological Kingsolver, J. G., and R. B. Huey. 1998. Evolutionary analyses
knowledge and concepts, ed. W. H. Dantzler (Section 13: of morphological and physiological plasticity in thermally
Comparative Physiology), vol. 1, 3–16. Bethesda, MD: variable environments. American Zoologist 38: 545–560.
American Physiological Society. Kleiber, M. 1975. The fire of life, 2nd ed. Huntington, New
Calder, W. A., III. 1984. Size, function, and life history. York: Krieger.
Cambridge, MA: Harvard University Press. Prosser, C. L. 1986. Adaptational biology: Molecules to
Crespi, B. J. 2000. The evolution of maladaptation. Heredity organisms. New York: Wiley.
84: 623–639. Schmidt-Nielsen, K. 1984. Scaling: Why is animal size so
Endler, J. A. 1986. Natural selection in the wild. Princeton, important? Cambridge: Cambridge University Press.
NJ: Princeton University Press. West, G. B., J. H. Brown, and B. J. Enquist. 1999. The fourth
Feder, M. E., A. F. Bennett, and R. B. Huey. 2000. dimension of life: Fractal geometry and allometric scaling
Evolutionary physiology. Annual Review of Ecology and of organisms. Science 276: 122–126.
Systematics 31: 315–341. Wieser, W. 1984. A distinction must be made between the
Garland, T., Jr., and P. A. Carter. 1994. Evolutionary ontogeny and the phylogeny of metabolism in order to
physiology. Annual Review of Physiology 56: 579–621. understand the mass exponent of energy metabolism.
Gibbs, A. G. 1999. Laboratory selection for the comparative Respiratory Physiology 55: 1–9.
physiologist. Journal of Experimental Biology 202:

Credits listed in order of appearance.
1 Photo Researchers, Inc., Francois Paquet-Durand/Photo
Researchers, Inc.
2 Frans Lanting/National
Geographic Stock.
3 Minden Pictures, FRANS LANTING/Minden Pictures.
3 Jonathan Blair-Corbis.

Chemistry, Biochemistry, and Cell Physiology
About 4.5 billion years ago the planet Earth coalesced from with the capacity for catalysis and self-replication. At some
clumps of debris floating through space after the Big Bang. point around 4 billion years ago, these purely chemical
For another billion years Earth’s surface was a harsh place; processes produced the earliest life-form, the progenote.
asteroid bombardment and volcanic eruptions were con- The progenote was likely a chemoautolithotroph, capable of
stantly remodeling the face of the planet. Yet it was during surviving without oxygen and living on inorganic sources of
this tumultuous period that life on Earth began. Some re- energy and carbon. The closest living relatives to the
searchers believe that organic molecules arose from a pri- progenote are likely the archaea. These modern prokaryotes
mordial soup of methane, ammonia, and water, energized by can survive in the harshest environments that now exist on
atmospheric electrical discharges. Others believe that the Earth, such as sulfuric hot springs and deep-sea vents.
first organic molecules arose from chemical reactions of The progenote was the ancestor to all organisms on the
products of deep-sea volcanoes. Regardless of the origins of planet and, as a result, it is likely that many of the ubiquitous
the first small organic molecules, the pathway to living or- biological features arose in the progenote. The dependence
ganisms required the formation of larger macromolecules on water, the role of nucleic acids, the use of only 20 amino

From Chapter 2 of Principles of Animal Physiology, Second Edition. Christopher D. Moyes, Patricia M. Schulte.
Copyright © 2008 by Pearson Education, Inc. Published by Pearson Benjamin Cummings. All rights reserved.
A species of domain Archaea found in deep-sea vents.

acids in proteins, and the basic pathways of intermediary

metabolism are shared attributes of all living organisms.
Within the first billion years, the progenote gave rise to
three distinct types of organisms: eubacteria, archaea, and Connective tissue.
eukaryotes. Each lineage diversified independently over the
next 3 billion years. The two prokaryote lineages, eubacteria The transition from single-cell organisms to multicellu-
and archaea, remained single-cell organisms with little in- lar organisms occurred independently in the ancestors of
tracellular organization. In contrast, the ancestral eukary- plants, fungi, and animals. Each lineage found different so-
otes experienced evolutionary changes that resulted in the lutions to the challenge of building multicellular tissues.
production of membranous, subcellular compartments, The strategy used by fungi and plants relies on a cell wall for
thereby increasing intracellular organization. This began resistance to osmotic swelling and intercellular connec-
when the earliest eukaryotes found a way to package their tions. Animal cells, in contrast, found other solutions to
DNA into a membrane-bound compartment: the nucleus. these physical challenges. Na/K ATPase appeared early
Later, around 3 billion years ago, a eukaryote engulfed a bac- in animal evolution, enabling animal cells to regulate cell
terium that resembled a modern purple bacterium. Although volume, ionic balance, and osmotic balance. Collagen, one
the purple bacterium was probably ingested as food, it devel- of the vital proteins used to construct tissues, also arose
oped a symbiotic relationship with its host, replicating with very early in metazoan evolution. Once these physical asso-
the host cell. Over time, the bacterial endosymbiont lost its ciations were established, more elaborate pathways for in-
capacity to exist outside the cell, and the host cell became re- tercellular communication became possible and necessary.
liant on the metabolic contributions of the endosymbiont, the Even plants and fungi use chemical messengers to commu-
ancestor of mitochondria. By 2 billion years ago the diverse nicate, but animals possess much more complicated mech-
groups of protists were established. The protists include or- anisms for cell-to-cell signaling.
ganisms like the euglena (with features of both animals and We cannot understand the basis of animal diversity
plants), the trypanosomes (the single-cell flagellate para- without an awareness of the evolutionary origins of animals.
sites of blood that cause malaria), and amoebas (ciliated On the one hand, many cellular processes are similar across
cells that are the namesake of amoeboid movement). These broad taxa, so what we learn from studies on model species
protists were once called protozoans because they were of fungi and plants tells us a lot about how these features
considered to be primitive animals, but we now recognize the work in animals. On the other hand, each lineage evolved
protists to be a group of over 50 different phyla that emerged novel ways of using similar machinery to face the chemical
prior to the origins of the three main eukaryote kingdoms: and physical stresses imposed by the environment. By un-
plants, fungi, and animals. The term metazoan, which arose derstanding how different taxa solved similar problems, we
to distinguish multicellular animals from the single-cell pro- can better understand the constraints on animal cell func-
tozoans, is now used synonymously with “animal,” although tion and evolution. Modern animal physiology builds upon
some taxonomists separate sponges, the most primitive an- studies of organisms in diverse taxa to understand the cel-
imals, from true metazoans (eumetazoans). lular origins of diversity in animals.2

Chemistry, Biochemistry, and Cell Physiology

Overview entropy, states that the universe is becoming

more chaotic. Both laws describe the constraints
Physiology is the study of how animals work and that exist when energy is transferred between sys-
how they solve the challenges of surviving in the tems. With any spontaneous transfer of energy,
natural environment. Though we often think of some energy is diverted in a way that increases
animal physiology as a study of organs, systems, the entropy of a system, another form of energy.
and whole animals, it is important to recognize Although each chemical reaction conforms to
that reasons for many of these features can be these principles, living organisms are able to delay
traced back to underlying rules of chemistry, bio- the inevitable increase in chaos, or entropy. The
chemistry, and cell biology. Many of the properties survival of living organisms depends upon an abil-
of organs and systems emerge from regulation of ity to obstruct the natural processes that lead to
cellular processes, such as energy production, chemical breakdown.
membrane transport, cellular anatomy, and gene
expression (Figure 1). While the physiology of an
animal is much more than the sum of these molec-
ular and cellular processes, an awareness of how
cells work is vital to understanding complex phys- Energy is the ability to do work. In our world,
iological processes. gasoline is an important form of chemical energy.
We know that if the fuel tank of a car is full of gaso-
line, we have the potential to use this fuel to move
Chemistry the car from place to place. Burning the gasoline
causes the pistons in the engine to move, turning
In the purely chemical world, chemical reactions the drive-shaft and ultimately the wheels. This fa-
proceed according to the rules of thermodynam- miliar analogy illustrates many important princi-
ics. The first law of thermodynamics, also called ples that govern energy transfers or energetics.
the law of conservation of energy, states that en- The gasoline in the tank has potential energy
ergy can be converted from one form to another trapped within its chemical structure. When gaso-
but the total amount of energy in the universe is line is ignited, the resulting explosion releases
constant. The second law, also called the law of heat and carbon dioxide, moving the piston in its




Energy production Membrane transport

Cellular anatomy Gene expression

Figure 1 Cells and tissues Many cellular processes underlie physiological systems.

Chemistry, Biochemistry, and Cell Physiology

cylinder. This type of energy is kinetic energy, • Thermal energy is a form of kinetic energy
the energy of movement. that is reflected in the movement of parti-
The standard SI (Système International) unit of cles, and serves to increase temperature.
energy is the joule, although the imperial unit, the • Chemical energy is a form of potential en-
calorie, persists in the scientific literature. A joule ergy that is held within the bonds of chem-
is defined many ways, depending on the circum- ical structures.
stances. In electrical terms, a joule (J) is the amount
of energy used when 1 watt of power (W) is ex-
pended for the period of 1 second (1 J  1 W  sec). Food webs transfer energy
Conversely, a watt is defined as a joule per second. Most biological processes are essentially transfers
You are probably most familiar with the units of of energy from one form to another. When you see
energy from your household electrical bill, with and smell a rose, the perception is essentially a
energy consumption expressed in kilowatt hours cascade of chemical and electrical energy trans-
(1 kW  h  3.6 × 106 J). In more biological terms, fers between the sensory system and the brain. We
a piece of toast with butter has about 300 kJ of en- are more familiar with the concept of energy
ergy, which is enough energy to allow you to run transfers in the context of food webs. Plants cap-
for about 6 minutes or light a 100-watt bulb for ture the energy of photons and use it to create sug-
about 1 hour. ars. Herbivorous animals eat the plants, and
All energy is kinetic energy, potential energy, carnivores eat the herbivores. At each level, some
or a combination of both. However, in the context potential energy in the diet is assimilated to form
of biological systems it is more useful to classify animal tissues. Some potential energy is converted
types of energy by other categories. to heat, which is either lost to the environment or
retained within the animal. Dietary potential en-
• Radiant energy is energy that is released
ergy is also transferred to kinetic energy, when an-
from an object and transmitted to another
imals use nutrients to fuel locomotion. A portion of
object by waves or particles. The sun is the
the potential energy in the diet is locked in chem-
most obvious source of radiant energy,
ical structures that can’t be liberated by the ani-
emitting light that serves as an energy
mal, and is excreted in waste products. Light is the
source for photosynthetic organisms. Other
ultimate source of dietary energy for most ani-
forms of radiant energy occur in animals,
mals; it also provides the energy that allows ani-
such as the infrared radiation given off
mals to use vision and perceive color.
from warm-bodied objects. Radiant energy
The chemical energy transferred between
is important in the thermal biology of ani-
trophic levels is stored within molecules in the
bonds between atoms. Chemical reactions liberate
• Mechanical energy is a combination of po- energy from one bond in order to produce other
tential and kinetic energy that can be used bonds. We discuss the nature of chemical bonds,
to move objects from place to place. A flying and the role of energy in bond formation, a bit
bird uses its wings to produce the mechan- later in this chapter. However, other forms of en-
ical energy necessary for flight. A kangaroo ergy are also critical components of biological
uses its legs to store mechanical energy in function.
the form of elastic storage energy. Recoil
of the springs helps the kangaroo hop.
Many forms of mechanical energy have im- Energy is stored in electrochemical
portant roles in animal locomotion. gradients
• Electrical energy is a combination of po- Molecules within a system tend to disperse or
tential and kinetic energy that results from diffuse randomly within the available space. Imag-
the movement of charged particles down a ine starting a dozen spinning tops in the center of
charge gradient. a box. The tops collide frequently at first, eventu-
ally dispersing randomly throughout the box.
Two aspects of diffusion govern the proper-
ties of many biological processes. First, diffusion is

Chemistry, Biochemistry, and Cell Physiology

certain to lead to a random distribution of mole- is expressed in the electrical unit of volts. In cells,
cules, but the rate of diffusion can be slow. Many membranes are the electrical barrier and the elec-
physiological systems function to reduce the re- trical gradient is called the membrane potential.
liance on slow rates of diffusion. Second, the ten- The nature of the molecule determines
dency of molecules to diffuse is a source of energy whether the potential energy of the gradient is pri-
that cells can use to drive other processes. Living marily electrical or chemical. If a molecule is un-
organisms can invest energy to delay the in- charged, then it can only form a chemical
evitable tendency toward randomness. In the pre- gradient. A charged molecule can form a chemical
vious example, you could prevent the spinning gradient and influence the electrical gradient. For
tops from randomly distributing by moving each instance, if the concentration of Na is greater out-
top back to the center position. Your efforts to re- side the cell than inside, there is both an electrical
verse the random distribution reflect an energetic gradient (more positive charges outside the cell)
investment on your part. Similarly, biological sys- and a chemical gradient (more Na ions outside
tems can invest energy to move molecules out of a the cell). Consequently, these gradients are often
random distribution. The resulting diffusion gra- discussed as electrochemical gradients.
dient is a form of energy storage that the cell can
use for other purposes. Of particular importance
are the gradients established across biological
Thermal energy is the movement
membranes. Transmembrane gradients created
of molecules
by cells differ in terms of the nature of the mole- It is impossible to ignore the importance of ther-
cules (Figure 2). A chemical gradient arises mal energy, or heat energy, in discussing chemical
when one type of molecule occurs at a higher con- or biological processes. When a system gains ther-
centration on one side of a membrane. The mag- mal energy, there is an increase in the movement
nitude of the chemical gradient is expressed as a of molecules within that system. This type of
ratio of the concentrations of the specific molecule movement has a profound effect on molecular re-
on either side of the membrane. For example, you activity and the rate of chemical reactions.
might say that a given molecule is 10-fold more Most chemical reactions involve changes in
concentrated outside the cell. The second type of thermal energy. Exergonic reactions release en-
gradient, an electrical gradient, arises if the dis- ergy and endergonic reactions absorb energy. To
tribution of charged molecules is unequal on ei- understand the reasons for these changes in energy,
ther side of an electrical barrier in a circuit. The let’s consider a simple reaction in which a single
electrical gradient across the barrier is dependent substrate, S, becomes a single product, P:
on the distributions of all the charged molecules
combined. The strength of the electrical gradient
At any given time, each molecule
of S is vibrating in solution, experi-
Positive charge
Negative charge
encing subtle changes in its struc-
+ + ture. A single molecule of S at times
+ + moves quickly (lots of kinetic energy)
and at other times moves slowly
+ +
(less kinetic energy). Occasionally, a
membrane molecule of S has so much kinetic
+ +
energy that it is able to assume a
+ + specific structure that is vulnerable
to a more significant change. This
+ + structure, intermediate between P
+ + and S, is called the transition state.
The energy required for a molecule
(a) Chemical gradient (b) Electrical gradient to reach the transition state is the
Figure 2 Storage of potential energy in electrochemical gradients activation energy, or EA. Once a
Animals can use the energy stored as (a) chemical gradients or molecule reaches the transition
(b) electrical gradients, or membrane potential. state, it is equally likely to revert to

Chemistry, Biochemistry, and Cell Physiology

the substrate, S, or convert to the product, P. The All chemical reactions are reversible under the
progression of the reaction from S to P, expressed right conditions. The reaction of S to P is favored
in terms of energy content, is shown in Figure 3. only because the activation energy barrier is lower
Since the free energy content, (G), of S is greater for S than it is for P. Because free energy was re-
than the free energy of P, the chemical reaction leased when S was converted to P, free energy
leads to a change in free energy (G), calculated must be absorbed if P is to be converted to S. The
as reverse reaction, with its positive G, is an ender-
gonic reaction. If both S and P are present, at any
G  Gproducts  Gsubstrates
point in time both forward and reverse reactions
In this reaction (Figure 3), P has a lower free en- occur simultaneously. The net reaction is the dif-
ergy, making G negative. S is converted to P, and ference between the forward rate and the reverse
the difference in free energy, or G, is released to rate. Because energy is released in one direction
the environment, primarily as heat. Thus, an ex- and absorbed in the other, the balance between
ergonic reaction is defined in thermodynamic forward and reverse directions depends on tem-
terms as a reaction with a negative G. An ender- perature. At high temperatures, endergonic reac-
gonic reaction has a positive G. tions become more feasible. Thus, temperature
influences chemical reactions in two ways. In-
creasing temperature allows more molecules to
reach activation energy, and increases the likeli-
Number of S molecules

hood of endergonic reactions.

Chemical Bonds
Most biologically available energy is stored in the
form of chemical bonds. Covalent bonds hold in-
dividual atoms together to form a molecule. These
Low EA High strong bonds involve the sharing of electrons be-
Enthalpy of S molecules tween two atoms. Noncovalent bonds organize
(a) molecules into three-dimensional structures. In
general, noncovalent bonds are called weak
bonds or sometimes weak interactions to further
distinguish them from strong bonds.
Transition state
Free energy (kcal/mol)

Activation Covalent bonds involve shared electrons

S energy (EA )
Each element has a characteristic arrangement of
electrons that influences the types of bonds it can
Difference in form. Specifically, for the six common biological
P E content of elements, each atom has at least one unpaired
substrate and
product (ΔG) electron in its outer electron shell. Atoms with un-
Chemical reaction paired electrons can readily form covalent bonds
with other atoms with unpaired electrons. These
atoms share electrons so readily that they are
Figure 3 Chemical reactions, substrates, rarely present in elemental form. Atoms with
products, and thermal energy (a) A collection of
more than one unpaired electron can form multi-
substrate molecules, S, possesses an average energy level and
ple covalent bonds. For instance, molecular oxy-
an average arrangement of electrons around its nucleus. But
at any given time, some S molecules are energy-rich and
gen has two oxygen atoms joined by a double
others energy-poor. (b) Occasionally a molecule of S might covalent bond. Many atoms are covalently bonded
absorb enough energy from the surroundings (perhaps from a to more than one other atom. Methane, for exam-
molecular collision) that it achieves the transition state (S*). At ple, is composed of four hydrogen atoms cova-
this point it could revert to S, or change into a novel product P. lently bound to a single carbon atom. Each type of

Chemistry, Biochemistry, and Cell Physiology

covalent bond has a characteristic bond energy, lecular interactions: van der Waals forces, hydro-
the energy required to either form or break the gen bonds, ionic bonds, and hydrophobic bonds
bond. The greater the bond energy, the stronger (Figure 5).
the bond. Multiple bonds possess more bond en- The electrons in a bond between two atoms
ergy than single bonds. Large molecules are built can be shared unequally. This asymmetry in elec-
from a collection of individual atoms attached by tron distribution creates a polarity, or transient di-
covalent bonds. Functional groups are combina- pole, within the molecular structure. One region is
tions of atoms and bonds that recur in biological slightly negative (), and the other is slightly pos-
molecules (Figure 4). itive ().
When an atom with a transient dipole encoun-
ters another atom, the distribution of electrons in
Weak bonds control macromolecular the second atom is altered. The weak interaction
structure between the two dipoles is the van der Waals in-
Weak bonds arise between atoms with asymmet- teraction. Van der Waals interactions are effec-
rical distributions of electrons either within the tive only over a very narrow range of atomic
atom or between atoms. Four types of weak bonds distances. When two atoms are far away, the di-
can be distinguished based on how they form mo- pole of one atom has no effect on the electron
cloud of the other. As the atoms approach, the at-
traction between the atoms increases. When the
Functional groups Covalent bonds atoms get too close, their electron shells repel each
O atom away from the other. The van der Waals ra-
dius is the distance at which the attractive force is
C OH Carboxyl S S Disulfide
at its greatest. Each atom has a characteristic van
der Waals radius.
Hydrogen bonds arise from the asymmetric
H sharing of electrons between two atoms. They are
N H Amino C O Ester critical to the organization of water molecules. In
a single water molecule, each hydrogen atom is
covalently linked to the oxygen atom. However, the
O O oxygen atom is just a bit better at attracting the

OH Hydroxyl P O P Phosphodiester

OH OH van der Waals interaction Hydrophobic bond

C H Methyl C S Thioester
Hydrogen bond H C H H C H


C O C Ether H C H H C H
P OH Phosphoryl
Ionic bond
SH Sulfhydryl N C Peptide H C H
+ –O C

Figure 4 Important functional groups and Figure 5 Weak bonds Four types of weak bonds are
bonds Although there are many types of bonds and involved in building macromolecules: hydrogen bonds, ionic
functional groups, those illustrated here are particularly bonds, van der Waals forces, and hydrophobic interactions.
common in macromolecular structure.

Chemistry, Biochemistry, and Cell Physiology

electron of hydrogen. More precisely, hydrogen’s Weak bonds are sensitive to temperature
electron spends a bit more time closer to the oxy-
Bond energy reflects the amount of thermal energy
gen atom than the hydrogen atom. Consequently,
required to break (or form) a bond. Weak bonds are
the hydrogen is slightly positive (), and the oxy-
more vulnerable to the effects of temperature be-
gen atom slightly negative (). The attraction be-
cause their bond energies are much lower than the
tween the  of hydrogen in one water molecule
bond energies of covalent bonds. Whereas covalent
and the  of oxygen in another water molecule
bonds have energies of formation of 200–900
constitutes a hydrogen bond (Figure 6).
kcal/mol, weak bonds have energies of formation
In some cases, a nucleus is so good at attract-
less than 5 kcal/mol. The three-dimensional macro-
ing electrons that when a bond breaks, an electron
molecular structures of proteins, membranes, and
from one atom remains with the other to create
DNA, which primarily depend upon weak bonds,
ions. Electronegative ions, or anions, possess ex-
are also sensitive to temperature. As a result, rising
tra electrons, whereas electropositive ions, or
temperature can cause macromolecules to unfold,
cations, have lost electrons. Anions and cations
or denature, when these weak bonds break. How-
can interact to form an ionic bond. Most of the
ever, not all weak bonds are affected by tempera-
molecules we think of as salts, acids, and bases
ture the same way. Hydrogen bonds, ionic bonds,
rely on ionic bonds to join anions and cations.
and van der Waals forces each have positive energy
Van der Waals forces, hydrogen bonds, and
of formation and tend to break when temperature
ionic interactions form on the basis of mutual at-
increases. In contrast, hydrophobic bonds have
traction between two charged or slightly charged
negative energy of formation and are strengthened
atoms. However, hydrophobic bonds form be-
by thermal energy.
tween atoms because of a mutual aversion to wa-
ter. Whole molecules or specific regions of large
molecules can be hydrophobic (“water-fearing”).
The bonds within hydrophobic molecules share 2 C O NC E P T C H E CK
electrons equally and therefore do not possess sig- 1. What are the five main forms of energy used by
nificant dipoles. With little internal charge, they animals? Provide biological and nonbiological
cannot interact effectively with the more polar examples of processes that represent conversion
molecules such as water. of energy from one form to another.
2. What are the four types of weak bonds, and
how do they differ from each other and from
covalent bonds?
δ– 3. What is the difference between (a) thermal
energy and temperature and (b) exergonic and
H δ+ H
δ+ H δ+

δ– H δ+ δ– H δ+
O Properties of Water
δ+ Most cells are composed primarily of water. Aquatic
H organisms also live in water, and even the cells of
δ+ H δ+ δ+
O δ– terrestrial organisms are bathed in the aquatic en-
vironment of their extracellular fluids. Many physi-
O H δ+ ological processes arose to meet the challenges of
the physical and chemical properties of water.
The properties of water are unique
Figure 6 Water dipole and hydrogen bonds
Oxygen atoms in water strongly attract the electron of the
A solvent is the most abundant molecule in a liquid,
hydrogen atom. The result is a small charge difference (). whereas the other molecules within the liquid are
The hydrogen atom is slightly positive () and the oxygen solutes. Collectively, the solutes and solvents con-
atom is slightly negative (). These charges influence the stitute the solution. In biological systems, the sol-
way that water molecules interact. vent is usually water. Water’s unusual combination

Chemistry, Biochemistry, and Cell Physiology

of physicochemical properties, which can be attrib- dense than liquid water and tends to float. These
uted to its ability to form hydrogen bonds, have physical properties of water have important ef-
special significance in biological processes and con- fects on aquatic ecosystems. In temperate regions
strain the direction of biological evolution. Liquid of Earth, a layer of ice forms on the surface of lakes
water is actually a network of interconnected wa- in early winter. The ice layer insulates the lake wa-
ter molecules. Each water molecule interacts ter from the air conditions, creating a more stable
strongly with other water molecules, creating in- environment for aquatic organisms. Temperature
ternal cohesiveness. At the interface between air also alters the density of liquid water. Because the
and water, the attraction between water molecules density of water is greatest at 4°C, the deepest
creates a force called surface tension. This pre- parts of large water bodies tend to be a constant
vents most water molecules from spontaneously 4°C, whereas surface waters can be colder or
escaping to the air. Many animals take advantage warmer, depending on the latitude and season.
of surface tension to move over water (Figure 7). Other physical properties of water have an im-
Their mass exerts a force on the water, but it is not portant impact on biological processes. Water has
great enough to disrupt the molecular interactions a higher melting point (0°C) and a higher boiling
between water molecules. point (100°C) than other solvents. In most habit-
The organization of water molecules changes able locations on Earth, then, water is a very sta-
in relation to temperature. At high temperatures, ble liquid. Water’s high heat of vaporization, the
the water molecules possess enough thermal en- amount of energy required to cause liquid water to
ergy to escape the restraining force of surface ten- boil or evaporate, makes sweating an effective
sion. At this point, the water “boils,” and water cooling strategy for mammals. A great deal of en-
molecules can escape as gaseous water (steam). In ergy is absorbed when liquid water vaporizes. Wa-
contrast, low temperatures stabilize water struc- ter on the skin absorbs a lot of thermal energy
ture as a result of the formation of additional hy- from the body in the process of evaporation.
drogen bonds. Water solidifies, or freezes, when
each water molecule forms four hydrogen bonds
to create a stable lattice of water molecules.
Solutes influence the physical properties
Changes in temperature also influence the
of water
density of water. Although frozen water molecules Many solutes can dissolve in water because they
incorporate more hydrogen bonds, the geometry can form hydrogen bonds with water molecules.
is such that the water molecules are held further Water-soluble molecules in solution are often sur-
apart than in liquid water. Consequently, ice is less rounded by a coat of water molecules called the
hydration shell. The hydration shell increases
the functional size of the molecule, and influences
how the solute interacts with other molecules in
complex biological systems.
In the tissues of most animals, the most com-
mon solutes are inorganic ions. K is the most abun-
dant cation inside cells, and Na is the most
abundant cation in the extracellular fluid. However,
in some species, particularly marine animals, the
most abundant solutes are organic ones such as
urea, amino acids, and sugars. Each type of solute
can exert specific, distinct effects on the chemical
properties of other molecules within the solution.
However, all solutes, regardless of their chemical
nature, exhibit four basic properties, known as
colligative properties. Solutes reduce the freezing
Figure 7 Surface tension The basilisk lizard is able point of the solution, and increase the boiling point,
to run across the surface of water. The surface tension of the vapor pressure, and the osmotic pressure of the
water can support the lizard because the force is distributed solution. The colligative properties depend only on
over the large surface area of the feet. the concentration of solutes, not their size or charge.

Chemistry, Biochemistry, and Cell Physiology

In a solution with high concentrations of that forms around many molecules enlarges the
solutes, cooling to 0°C will not induce freezing. The functional size of the molecule, restricting its mobil-
thermal energy of the system is low enough to form ity. Other factors that influence how the solute inter-
the extra hydrogen bonds, but the solutes block the acts with the solvent, such as charge and solubility,
formation of hydrogen bonds necessary to form the also affect the rate of diffusion. Each solute has an
ice crystal. When solutes are present, the solution experimentally determined diffusion coefficient
must be cooled below 0°C before the extra hydro- (Ds), which is influenced by the structural properties
gen bonds can form. The freezing point of biologi- of the solute. The rate of diffusion of a solute (dQs /dt)
cal fluids, such as cytoplasm or blood, is always depends on the diffusion coefficient of the solute (Ds),
lower than freshwater, and sometimes even as low the diffusion area (A), and the concentration gradi-
as seawater. The difference in the freezing point of ent (dC/dX). The relationship between these param-
body fluids and the aquatic environment has im- eters is defined by the Fick equation:
portant ramifications for aquatic animals.
dQs dC
Similar mechanisms are responsible for the ef-  Ds  A 
dt dX
fects of solutes on the vapor pressure and boiling
point of water. A water molecule can escape liquid Small solutes, such as inorganic ions, are able
water only at the water-gas interface. When solute to traverse the width of the cell, typically about
molecules are also present at the surface, they re- 10 µm, in a fraction of a second. The time required
duce the likelihood that a water molecule will es- for a molecule to diffuse a given distance increases
cape. We discuss the fourth colligative property, with the square of the distance. If a molecule takes
osmotic pressure, after we discuss a related con- 1 sec to diffuse 0.1 mm, it would take about 3 h to
cept: diffusion. diffuse 1 cm. Many biological processes depend on
diffusion, such that physiological and anatomical
strategies have evolved to prevent these processes
Solutes move through water by diffusion from becoming “diffusion limited.”
The direction of diffusion of molecules in a solution
depends on the concentration gradient, but the rate
of diffusion depends on many additional factors.
Solutes in biological systems impose
Molecules move more rapidly when the gradients
osmotic pressure
are steeper. The properties of the solute itself also in- The semipermeable membranes of cells allow
fluence the rate of diffusion. If solute molecules are some molecules to cross while restricting the
relatively large, they have a more difficult time mov- movement of others. Imagine a situation where
ing through the restrictive structure of water. Large two identical solutions of pure water exist on ei-
molecules like proteins diffuse much more slowly ther side of a membrane that allows free move-
than small molecules like K. The hydration shell ment of water molecules only (Figure 8). On each


H2O H2O pressure

(a) (b) (c) (d)

Figure 8 Osmotic pressure The two solutions differing in solute concentration are
separated by a semipermeable membrane. The movement of water creates osmotic pressure.
Movement will continue until the force of gravity is equal to the osmotic pressure.

Chemistry, Biochemistry, and Cell Physiology

side of the membrane is approximately 55.5 mol tion is hyposmotic. When the osmolarity is the
of water per liter. Water molecules freely cross the same on both sides of the cell membrane, the so-
membrane in both directions. If you added NaCl to lution is isosmotic.
one side of the membrane, a concentration gradi-
ent would be created for Na and Cl. Since the Differences in osmolarity can alter cell
membrane is permeable to water alone, only wa- volume
ter molecules could move across to equalize the
Biologists usually make distinctions between os-
concentration gradients. There would be a net
molarity, which is related to the osmotic pressure,
movement of water molecules from the side with
and tonicity, which is the effect of a solution on
pure water to the side with solutes. This would in-
cell volume. Tonicity depends on differences in os-
crease the volume on the side with solutes. Even-
tually, the net movement of water would stop molarity, but also on the types of solutes and the
permeability of the membrane to those solutes.
when the force generated by the movement of wa-
To understand the distinction between osmo-
ter equaled the force of gravity, which prevents the
larity and tonicity, consider the following example
water column from getting any higher. In cells, the
(Figure 9b). A cell that is placed in an isosmotic
movement of water is restricted not by gravity but
salt solution neither shrinks nor swells (an
by the flexibility of the cell membrane. In either
case, the force associated with the movement of isotonic solution). If more salt is added, the cell
loses water and shrinks. Thus, this solution is both
water is the osmotic pressure, the fourth colliga-
hyperosmotic and hypertonic. Imagine now that
tive property of solutes.
small amounts of urea, a permeant solute, are
The ability of solutions to induce water to
added to the isotonic salt solution. The urea would
cross a membrane is expressed as the osmolarity,
equilibrate across the cell membrane, and thus
expressed in units of osmoles per liter (OsM). Os-
prevent the net movement of water in or out of the
molarity is analogous in many respects to molar-
cell; this is an isotonic solution. Of course, if the
ity (M). Whereas molarity is a reflection of the
concentration of specific molecules in a solution, cell were placed in a solution containing only urea,
the movement of urea into the cell, combined with
osmolarity depends on the total concentration of
the high internal salt concentration, would draw
particles in solution. The osmolarity of a solution
water into the cell, causing it to swell or even
of known molarity can be calculated on the basis
of the number of particles derived from each mol- burst; this is a hypotonic solution.
ecule. If a solution has only one solute, and that
solute does not dissociate, then molarity and osmo-
larity are equivalent. For instance, 1 mol/l (or 1 M) pH and the Ionization of Water
glucose solution has an osmolarity of 1 osmol/l (or A small proportion of the H2O molecules in any so-
1 OsM). Some solutes dissociate into multiple par- lution dissociates into ions by breaking one of the
ticles. Each mole of NaCl produces 1 mol of Na covalent bonds between oxygen and hydrogen. In
and 1 mol of Cl. Thus, a 1 M NaCl solution has an reality, water is in equilibrium with itself.
osmolarity of 2 OsM. Knowledge of the concentra-
H2O  H2O Δ H3O  OH
tion and valency of the solutes would allow you to
estimate osmolarity, but in reality the osmolarity is For simplicity, the cation is treated as a proton
somewhat less. Some of the salt does not dissoci- (H) rather than a hydronium ion (H3O). The dis-
ate, and some of the water molecules become as- sociation of water into ions is reversible. Both the
sociated with the hydration shell of the ions. The forward reaction (water dissociation) and the re-
osmolarity and osmotic pressure of a solution are verse direction (water formation) occur simultane-
physical properties of a solution. However, in a bi- ously. Only a very small proportion of water
ological setting the absolute osmolarity is often molecules are dissociated at any given time, about
less important than the osmolarity of an extracel- 1 in 55,500,000 water molecules at room temper-
lular fluid relative to the osmolarity of the intracel- ature (25°C). Under these conditions (pure water
lular fluid (Figure 9a). If a cell is placed in a at 25°C), the concentration of protons arising from
solution with greater osmolarity, then the solution water dissociation is 107 M. For the sake of con-
is considered hyperosmotic (relative to the cell). venience, the concentration of protons is usually
Similarly, if a cell is placed in pure water, the solu- converted to the pH scale. The pH of a solution is

Chemistry, Biochemistry, and Cell Physiology

Na+ Na+

Cl– Cl–
Cell Cell

Isosmotic Isotonic
Solution Solution
More salt More water Salt Urea
added added added added


Hyperosmotic Hyposmotic Hypertonic Isotonic

Solution Solution Solution Solution
(a) Osmolarity (b) Tonicity

Figure 9 Osmolarity versus tonicity (a) A cell is swell. (b) The effects of solutes on cell volume depend on the
in an isosmotic solution when the solution has an osmotic ability of the solute to enter the cell. If NaCl is added to an
pressure equal to that of the cell cytoplasm. If salt is added to isosmotic solution, the cell shrinks and the solution is
the solution it becomes a hyperosmotic solution. Water leaves considered hypertonic. If urea is added to the solution, there is
the cell, causing the cell volume to shrink, until the osmotic little change in cell volume because urea can cross the cell
pressures are again equal. If the salt concentration is reduced, membrane. Thus, adding urea to this solution makes it
as would be the case if more water was added, the solution hyperosmotic, but it is also isotonic.
becomes hyposmotic. Water flows into the cell, causing it to

calculated as the negative logarithm of proton con- molecules dissociate, raising the pH to 7.28. In
centration (denoted as [H]). Thus, the pH of pure each of these situations, water remains neutral,
water at 25°C is pH 7 (log 107). As we see later but the pH at neutrality, or pN, varies inversely
in this chapter, the negative logarithmic scale, des- with temperature. In practice, pure water changes
ignated by the prefix p, is also a convenient way to its pH at a rate of 0.014 units per degree Celsius.
express low concentrations of other ions, such as
pOH for [OH] and pCa for [Ca2].
Acids and bases alter the pH of water
Pure water is never anything but neutral. How-
Neutrality is not always at pH 7 ever, ionizable solutes can influence the pH of a so-
A solution is considered neutral when [H]  lution. An acid releases one or more protons.
[OH], or pH  pOH. Pure water at 25°C possesses Hydrochloric acid (HCl) is an acid because it disso-
107 M concentrations of both H and OH: pH  7 ciates into H and Cl. A base causes a reduction
and pOH  7. The temperature of a solution of in the [H] of the solution. When the base sodium
pure water alters the proportion of water mole- hydroxide (NaOH) is dissolved into water, it rap-
cules with enough thermal energy to break the co- idly dissociates into Na and OH. The extra OH
valent O–H bond. For instance, at 45°C almost arising from NaOH dissociation rapidly interacts
twice as many H2O molecules dissociate, lowering with H to form H2O, reducing the [H] and in-
the pH to 6.72. At 5°C, about half as many H2O creasing pH.

Chemistry, Biochemistry, and Cell Physiology

The degree to which acids and bases change This simple equation is useful for understand-
the pH of a solution depends on the ease with ing many different biochemical and physiological
which the molecule dissociates under physiologi- principles. For example, the pK value reflects the
cal conditions. Inorganic acids such as HCl and strength of acids and bases. A strong acid will give
H2SO4 are considered strong acids because they up its proton even when the concentration of pro-
readily release their protons to the solution. Simi- tons in the surrounding area is very high (low pH).
larly, NaOH and KOH are strong bases because Thus, the pH must be very low to prevent a strong
they readily dissociate to release OH. Many bio- acid from dissociating. The pK value is low for a
logical molecules are weak acids or weak bases, strong acid, less than 3 for hydrochloric acid and
which are only partially ionized under physiologi- sulfuric acid. Similarly, strong bases, such as
cal conditions. sodium hydroxide and ammonium hydroxide,
If an acid is defined as something that releases have pK values greater than 11. The pK values for
a proton, then we can discuss acids with the gen- some common biological acids and bases are
eral formula of HA. Dissociation of the acid HA shown in Table 1.
produces H and the anion, A. We can describe a The equilibrium equation is a powerful tool for
reversible chemical reaction with the equation analyzing biological solutions. Once we know the
HA Δ H  A values of three of the four parameters, we can cal-
culate the one that is unknown. To determine pH,
We define the relationship between the sub- we can rearrange the equation into the form
strate (HA) and products (H and A) as the mass
3A 4
action ratio, using the equation pH  pK  log
3 HA 4
3H 4  3 A 4
Mass action ratio 
3HA 4
This rearrangement is known as the
Henderson-Hasselbalch equation, named after
To understand how these parameters change, the researchers who used the relationship to ex-
consider an experiment where the acid HA is added plain the behavior of CO2 (HA) and HCO3 (A),
to pure water. When first added to water, HA re- which is important in respiratory physiology.
mains intact and [A] is equal to zero; the mass ac-
tion ratio is also close to zero. However, very
quickly at least some of the acid dissociates. There Table 1 Acids and bases.
is an increase in both [H] and [A], and as a result
an increase in the mass action ratio. At some point Acid Reaction pK
the reaction slows, with [HA] reaching a minimum  
Carbonic acid H2CO3 → HCO3  H 3.8
and [H] and [A] reaching a maximum. When this 
HCO3 → CO3 H 
occurs, the reaction is at equilibrium. It is impor-
tant to recognize that although there is no net Phosphoric acid H3PO4 → H2PO4  H 3.1
change in the concentrations of reactants, both for- H2PO4 → HPO42  H 6.9
ward and reverse reactions continue, but at equal 
HPO4 2
→ PO43 H 12.4
rates. When the reaction is at equilibrium, the
mass action ratio attains a specific value, Keq, the Ammonium NH4 → NH3  H 
equilibrium constant. Under most circumstances, Acetic acid CH3COOH → CH3COO  H  
the equilibrium constant is converted to its negative
Glycine (amino) R–NH3 → R–NH2  H 2.3
log (log10 Keq), analogous to the way we converted
[H] to pH. Thus, the equilibrium equation can be (carboxy) R–COOH → R–COO  H 9.6
rewritten after log transformation as H H
3A 4

pK  pH  log
3HA 4 Histidine R – C CH R–C CH + H+ 6.0
Put another way, the pK is the pH at which half the
acid is dissociated, [A]  [HA], [A]/[HA] 1 and H+
log [A]/[HA]  0.

Chemistry, Biochemistry, and Cell Physiology

Both pH and temperature affect the of the glycine molecule, or its pKCOOH. Adding more
ionization of biological molecules base causes deprotonation of the amino group. At
pH 9.6, exactly half the amino groups are proto-
Changes in pH can alter the dissociation of other
nated. This pH value is the equilibrium constant
molecules with ionizable groups. Let’s look at the
for the amino group of glycine, or its pKNH2. At still
amino acid glycine to explore how pH affects its
higher pH values, the carboxyl groups remain
structure (Figure 10). Glycine has a carboxyl
charged and the amino groups are fully deproto-
group that can be protonated (–COOH) or deproto-
nated, giving the glycine molecule a net negative
nated (–COO). It has an amino group that can be
charge. Midway between the two pK values, the
deprotonated (–NH2) or protonated (–NH3). The
glycine molecule has no net charge, as the charges
protonation state of the carboxyl and amino
on the carboxyl group (COO) balance the charges
groups in a molecule of glycine depends on the pH
on the amino group (NH3). Glycine and other mol-
of the solution.
ecules that have both negative and positive
We can observe the effects of pH on glycine
charges are called zwitterions.
structure by performing a titration, where an acid
The ionization state of molecules is very sensi-
or base is added to a solution. We start our titra-
tive to temperature. Let’s return to the previous ex-
tion by dissolving glycine in an acidic solution. At
ample where we titrated the ionizable groups of
very low pH, where [H] is high, both amino and
glycine. As pH rose to equal pKCOOH, protons became
carboxyl groups are protonated. The carboxyl
so scarce that half of the carboxyl groups lost their
group is uncharged (–COOH) and the amino group
proton. If we repeated the titration at lower temper-
has a positive charge (–NH3), giving glycine a net
ature, the pK value would change because the lower
positive charge. When we add base to the solution
temperature increases the strength of the bond
to increase pH, the protonation state of both of
holding the proton to the carboxyl group. At any
these groups begins to change. First, the carboxyl
given pH the colder glycine would be more proto-
groups become deprotonated (–COOH → –COO2 
nated. Put another way, a higher pH would be re-
H). At pH 2.3, exactly half of the carboxyl groups
quired to lure half the protons off the carboxyl
in the glycine molecule are ionized. This pH value
group. Thus, the pK value increases as temperature
is the equilibrium constant for the carboxyl group
decreases. Each ionizable group has a characteristic
sensitivity to temperature, ex-
14 pressed as pK/°C. For example,
13 H H
H H the ionization of phosphoric acid
12 N
O is relatively insensitive to tem-
11 H C C = H C C
– perature (pK/°C  0.005),
O– O
10 H
H whereas the ionization of the
9 pKa = 9.6 imidazole group of histidine is
8 more sensitive to temperature
(pK/°C  0.017).

+ +
7 H H
6 N
The protonation state of
5 H C C
many molecules can have im-
=H C C
4 OH O
– portant effects on molecular
3 processes. Many of the effects of
2 pKa = 2.3 temperature and pH on cells
can be traced to the effects on
the protonation state of critical
Added base molecules. For example, many
proteins form structures that
Figure 10 Changing pH and the ionization state of acids and bases
The amino acid glycine occurs in several different ionization states that change with
depend on particular ionization

pH. At low pH (high [H ]) both the amino group and the carboxyl group are protonated. states of amino acids. Changes
As pH increases, the carboxyl loses its proton first, becoming half ionized at pH 2.3, its in pH or temperature can affect
pKa value. The amino group does not lose its proton until much higher pH values are how these proteins fold and
reached. Near neutral pH, glycine is primarily neutral. function. By actively regulating

Chemistry, Biochemistry, and Cell Physiology

temperature and pH, animals diminish the debilitat- some of the protons are liberated from acetic acid,
ing effects of changes in protonation state. the added NaOH has a reduced effect on the pH of
the solution. This buffering effect is evident over the
pH range of about 3.75 to 5.75, where the titration
Buffers limit changes in pH curve is quite shallow. Once pH reaches 5.75, most
A variety of mechanisms help cells regulate pH. of the acetic acid is in the deprotonated form (A),
The first level of defense is a buffer. A buffer is a which cannot act as a buffer. This pH range corre-
chemical found in a solution that dampens the ef- sponds to the greatest buffering capacity of the so-
fect of added acid or base on the pH of the solu- lution, and is centered on the pK value for the
tion. Buffers are often described as if they were buffer, about 4.75, where about half of the buffer is
single molecules. In reality we should think of protonated (HA) and half deprotonated (A).
them as buffer systems, because they are mixtures Animals use a variety of different molecules as
of at least two forms of a molecule, typically proto- buffers. The best buffers in animal cells have pK
nated and deprotonated. values that approach the pH of the compartment in
If we add a buffer to the solution, the protons which they are used. Phosphate (H2PO4 /HPO42)
liberated from the acid can associate with the is an important buffer in the cytoplasm of most
buffer. As a result, the addition of acid has less ef- cells, with a pKA of 6.9. The amino acid histidine
fect on pH than it does in the absence of buffer. Most contributes to buffering in many animal cells be-
buffer systems rely on weak acids, present in both cause the pK value of its imidazole side chain is
the acid form (HA) and the anion form (A). Fur- very close to intracellular pH. Histidine residues
thermore, a buffer works only over a particular within large proteins help buffer the cytoplasm
range of pH values. Acetic acid is a weak acid that against changes in pH. Many species use amino
can be used as a buffer. The effects of an acetic acids with imidazole groups to produce dipeptides
acid/acetate buffer are illustrated by the titration that serve as important intracellular buffers. The
curve shown in Figure 11. If you started your titra- dipeptides carnosine (histidine and -alanine),
tion at low pH, most of the acetic acid would be in anserine (1-methylhistidine and -alanine), and
the protonated form (HA). If you added small vol- ophidine (3-methylhistidine and -alanine) are
umes of NaOH, the pH would increase proportion- important buffers in the muscle of many species.
ately. Below pH 3.75, acetic acid would remain In air-breathing animals, the most important
mostly protonated (HA). If you add more base, the extracellular buffer is bicarbonate/CO2, but it
increase in pH would induce some acetic acid (HA) works by a different mechanism than a simple
to become deprotonated (HA → H  A). Since A/HA buffer pair. In a closed test tube bicarbon-
ate/CO2 would have little buffering capacity at
physiological pH because its pK is much too low
10 (3.8). It works as a biological buffer because ani-
9 mals can expire CO2. As [H] increases, bicarbon-
ate is consumed and carbonic acid is produced
(H2CO3), which in turn forms H2O and CO2.
H  HCO3 → H2CO3 → H2O  CO2
When an animal expires CO2 as a gas, it is es-

5 sentially eliminating a weak acid from the body,


4 buffering against a change in pH.

3 Same amount of
base has different
2 effects on pH.
4. What is the relationship between pK and pH?
0 5. How does temperature influence the pK of
Added base
water? What might this mean for animals that
Figure 11 Effects of buffers on changes in pH experience changes in body temperature?
Buffers blunt the effects of added bases (or acid) on the pH of
a solution.

Chemistry, Biochemistry, and Cell Physiology

6. What change in pH has a greater effect on proton that are metals, such as copper, iron, magne-
concentration: pH 6 to 7 or pH 7 to 8? sium, zinc, and selenium. Organic cofactors, or
7. What properties of a particle influence its rate of coenzymes, are usually derived from vitamins;
diffusion across a membrane? What membrane coenzyme A is derived from panthothenic acid,
properties influence this rate?
FAD from riboflavin, and NAD from niacin. Many
of the life-threatening diseases we associate with
vitamin deficiencies can be traced back to pertur-
Biochemistry bations of metabolism due to loss of function of
specific enzymes.
Animals control the inner workings of cells
through the use of enzymes, which interconvert
macromolecules to create building blocks and con- Enzymes accelerate reactions by reducing
trol the flow of chemical energy. A metabolic path- the reaction activation energy
way is a series of consecutive enzymatic reactions The laws of thermodynamics that govern chemical
that catalyze the conversion of substrates to prod- reactions in test tubes also apply to chemical reac-
ucts, with multiple stable intermediates. Flow tions in living cells (see Box 1, Mathematical Un-
through the pathway is called metabolic flux. derpinnings: Thermodynamics). Enzymes do not
Metabolic pathways can be either synthetic (ana- determine whether or not a chemical reaction is
bolic), degradative (catabolic), or a combination thermodynamically possible. However, enzymes
of both (amphibolic). Energy metabolism re- do have the ability to accelerate thermodynami-
volves around production of ATP and other energy- cally feasible reactions by factors of 108 to 1012.
rich molecules. Metabolism is the sum of all these Previously we discussed how substrate mole-
metabolic pathways within the cell, tissue, or or- cules in an uncatalyzed reaction must obtain suf-
ganism. Many metabolic pathways span multiple ficient energy to meet the activation energy
cellular compartments, allowing cells to create barrier (EA). Once the EA is met, the substrate can
distinct microenvironments. For example, the mi- adopt the transition state and then spontaneously
tochondria are specialized compartments with a change into the product. Although enzymatic re-
major role in energy metabolism. action uses the same substrate and yields the
In the following sections, we discuss the na- same product as an uncatalyzed reaction, it pro-
ture of enzymes and metabolic energy, and the duces a different intermediate at the transition
metabolism of three of the four major classes of bi- state. First, the enzyme (E) and substrate (S) bind
ological macromolecules: proteins, carbohydrates, to form the ES complex. After conversion to tran-
and lipids. The fourth class of macromolecules, sition states (ES*, EP*), the final product (P) is
nucleic acids, is discussed later in this chapter formed and then is released by the enzyme. This
when we consider genetics. is represented as shown:
The energy required to reach this intermediate
Enzymes state is lower than in the uncatalyzed reaction
Enzymes are biological catalysts that convert a (Figure 12). With a lower energy barrier, more of
substrate to a product. Enzymes, like other types the substrate molecules possess enough energy to
of catalysts, have three properties: (1) they are ac- reach the transition state, and the reaction is ac-
tive at very low concentrations within the cell; celerated. Like other chemical reactions, enzyme
(2) they increase the rate of reactions but they reactions are reversible, proceeding through the
themselves are not altered in the process; (3) they same set of reaction intermediates.
do not change the nature of the products. An enzymatic reaction begins with the sub-
Although some enzymes, called ribozymes, strate binding at a specific location called the
are made of RNA, most enzymes are composed of active site. Think of the active site as a pocket into
protein. Many enzymes possess nonprotein com- which the substrate fits. The enzyme can bind the
ponents, called cofactors. A cofactor that is cova- substrate only if it possesses the proper conforma-
lently bonded into the enzyme is called a tion. The three-dimensional folding of the enzyme,
prosthetic group. Some enzymes use cofactors maintained by weak bonds, forms the active site.

Chemistry, Biochemistry, and Cell Physiology



All chemical reactions, whether they oc- G. All reactions that occur spontaneously possess a
cur in test tubes or biological systems, are gov- negative G; free energy was released.
erned by the laws of thermodynamics. The first law of Chemists evaluate these parameters under standard
thermodynamics deals with conservation of energy. The conditions. The standard free energy, or G° is assessed
energy within a substrate is either transferred to the at 25°C, with each reactant, including H, present at a
product or released. The first law doesn’t tell us if the re- concentration of 1 M. The proton concentration used by
action will go forward or backward, only that the energy chemists equates to pH 0, which is not relevant to biolog-
transformations must be balanced. The second law of ical systems. When we use the laws of thermodynamics
thermodynamics provides a way of predicting if a reaction to discuss biological systems, the parameters must be
is likely to occur. It says that spontaneous processes altered to reflect normal cellular conditions. When bio-
occur in the direction that will increase randomness, or chemists adjust G for standard conditions, including a
entropy (S). Throughout this chapter we discuss many pH of 7.0, the symbol G°′ is used.
examples of increases in entropy. When table salt dis- It is important to distinguish between G and G°′
solves in water or ice melts, the molecules that were when discussing chemical reactions. The value of G°′ is
once in a well-ordered crystal begin to disperse. Diffu- a constant. It tells how much free energy is available when
sion also illustrates the principle of spontaneous in- a reaction begins under standard conditions. The value of
creases in entropy. Solutes at high concentration tend to G, the actual free energy of a reaction in a cell, depends
disperse to regions of lower concentration. Collectively, upon the concentrations of reactants. If a reaction is close
these laws tell us that the total energy of the universe is to equilibrium, then G equals zero. For the reaction
constant but that it tends toward randomness.
What does this mean for chemical reactions? As we
discovered earlier, spontaneous chemical reactions lib- the relationship between G, G°′, and concentration is
erate thermal energy. Some of this thermal energy is defined by the following equation where R is the gas
used within the system to increase randomness or en- constant:
tropy. The remainder of the thermal energy is called
free energy (G) because it is available for other pur- 3 Y4 3 Z4
¢G  ¢G°¿  RT ln
poses. The equation relating enthalpy (H), entropy 3A 4 3 B4
(S), free energy (G), and temperature (T) was first
When the reaction is at equilibrium G  0 and the mass
proposed by J. Willard Gibbs in 1878.
action ratio is equal to Keq, the equation is reduced to
H  G  T S
0  G°′  RT ln Keq
From this equation, we see two factors that influence bi-
ological systems. First, the change in energy associated or
with randomness is dependent upon temperature. This is G°′  RT ln Keq
because the potency of a fixed amount of thermal energy,
or its ability to induce randomness, depends on temper- We can measure Keq directly by letting the reaction
ature. Thermal energy is more effective at inducing en- reach equilibrium. The value of G°′ can be calculated
tropy at low temperature. The second principle is more from the equation above. Knowing Keq and G°′, we can
apparent if we rearrange the equation to isolate G. calculate the amount of actual free energy G available
for a reaction at any concentration of reactants.
G  H  T S
Remember that G represents the maximal amount
The amount of free energy available in a reaction is the of free energy theoretically available from a reaction,
difference between the total energy change and the under a constant temperature and pressure that ap-
amount of energy associated with the change in ran- proximates conditions found in the cell. Cells use en-
domness. This equation allows us to predict if a reaction zymes to mediate chemical reactions and transfer as
will occur spontaneously. If a reaction is to occur spon- much energy as possible to other useful forms. Some
taneously, the amount of energy potentially released by enzymes mediate reactions that store energy as chem-
a reaction (H) must be greater than the energy used to ical energy, such as ATP or NADH. Free energy can also
increase entropy (T S). Recall that exothermic reac- be used to create electrochemical gradients. The ability
tions, those that release heat, have a negative H. Sim- to divert free energy into useful forms is central to the
ilarly, reactions that release free energy have a negative success of living organisms.

Chemistry, Biochemistry, and Cell Physiology

EA (uncatalyzed)
Free energy

EA (catalyzed)

Change in
free energy
Slope = V = ( )

Time Time

Figure 12 Enzymes and EA Enzymes are biological Figure 13 Time course of enzyme reaction
catalysts that accelerate reactions without changing the Enzyme assays begin with the addition of substrate to the
nature of the product. When the substrate (S) binds the reaction. The enzyme rapidly converts the substrate (S) to
enzyme (E), the enzyme-substrate complex (ES) is formed. product (P). The buildup of [P] eventually slows the reaction,
The enzyme alters the substrate through a series of as P competes with S for the active site. The initial velocity (V)
transition states, ultimately releasing the product (P). The is the fastest because P has not yet accumulated.
rate is faster than the noncatalyzed rate because of the
lower activation energy (EA).
(S) or products (P). We use the reaction S → P to il-
lustrate the importance of substrate concentration
Once it binds the substrate, the enzyme induces a ([S]) in two experimental scenarios.
change in the molecular structure of the substrate, The first scenario illustrates how the buildup
perhaps as subtle as a shift in the distribution of of [P] influences the rate of the forward reaction
electrons across a particular bond or a twist in the (Figure 13). When the reaction begins, there is no
substrate molecule. By inducing these subtle product ([P]  0). As it proceeds, molecules of P ac-
structural changes in the substrate, the enzyme cumulate and eventually compete with molecules
makes the substrate more likely to spontaneously of S for the same active site. Finally, the reaction
undergo more significant changes. Many enzymes approaches equilibrium, where the forward and
require two or more substrates. These enzymes reverse reaction rates are equal and the mass ac-
accelerate reactions by bringing destabilized reac- tion ratio equals Keq. We can determine the initial
tants in close proximity. All together, these velocity of the forward reaction (V) from the slope
changes increase the probability that the substrate of the curve before P accumulates.
will undergo a major change in structure toward The second scenario illustrates how the initial
the formation of EP*. [S] influences the enzymatic rate (Figure 14). The
experiment previously described is repeated many
times using a wide range of starting [S]. Increasing
Enzyme kinetics describe enzymatic [S] from a low concentration to a higher concen-
properties tration causes a proportional increase in V. Under
Enzymes accelerate reaction rates, and make possi- these conditions, a higher [S] increases the fre-
ble reactions that would not normally occur at a use- quency with which molecules of S find the active
ful rate. However, cells must ensure that enzymatic site. However, after a point, increases in [S] no
reactions occur not at the fastest possible rate, but longer cause a proportional increase in V. The
at the appropriate rate. Thus, enzyme activity is reg- higher abundance of S molecules still increases
ulated within complex metabolic pathways. The the probability of a collision with E. However, if S
conditions that influence the rate of enzymatic reac- encounters E in the midst of a reaction cycle, the
tions are referred to as enzyme kinetics. enzyme is unable to bind S. Eventually, E is
The simplest way to influence an enzymatic re- saturated with S molecules and further increases
action is to change the concentration of substrates in [S] do not increase V beyond a maximal rate

Chemistry, Biochemistry, and Cell Physiology


Initial velocity (mmoles/min)

1/2 Vmax

Km [S]
Substrate concentration (mM)
Figure 15 Homotropic enzymes and sigmoidal
Figure 14 The Michaelis-Menten rectangular kinetics Not all enzymes obey Michaelis-Menten
hyperbola Each point on the curve represents the initial kinetics. Homotropic enzymes show sigmoidal kinetics. The
velocity (V) calculated as shown in Figure 16. The maximal enzymes usually possess multiple active sites. When the
velocity (Vmax) is the velocity at which the curve reaches an enzyme binds one molecule of S, the changes in
asymptote. The Km is the [S] required to reach a velocity that conformation increase the ability to bind a second molecule
is one-half of the maximal velocity. of S. The slope of the linear range of the curve indicates the
degree of cooperativity. The slope of this region provides the
Hill coefficient.
(Vmax). When enzymes are at Vmax, each molecule
of enzyme has a characteristic number of catalytic the enzyme has high affinity for the substrate, and
cycles per unit time, known as the turnover num- little substrate is needed to drive the reaction at a
ber or kcat. high rate.
A high rate of enzymatic activity could be Not all enzymes demonstrate hyperbolic
achieved by a cell, in principle, in either of two Michaelis-Menten kinetics. For instance, ho-
ways. Some enzymes work very fast, and show a motropic enzymes show a sigmoidal relationship
high kcat. The cell does not need many molecules between V and [S] (Figure 15). Homotropic en-
of the enzyme because each molecule works zymes typically have multiple subunits that can
quickly. The fastest enzymes can undergo more each bind a substrate molecule. At low [S], each ac-
than 40,000,000 catalytic cycles each second. Alter- tive site has a low affinity for S. The enzyme does
natively, cells can make many copies of an enzyme not bind S very well and the reaction velocity is
with a low kcat. The relative importance of each slow. Once one subunit binds one molecule of S, it
strategy—faster enzymes versus more enzymes— undergoes a change in conformation that in turn al-
depends on the nature of the reaction and the de- ters the ability of other subunits to bind a substrate
sign of the enzyme. molecule. As a result, doubling of [S] more than
The relationship between [S] and V was first doubles V, a phenomenon called cooperativity. The
described mathematically by the biochemists degree of cooperativity is described by the Hill co-
Leonar Michaelis and Maud Menten as a rectan- efficient, which is the slope of relationship at the
gular hyperbola. The Michaelis-Menten equa- point of inflection.
tion is Enzyme kinetics are assessed under carefully
controlled experimental conditions that do not ap-
V  VMAX  proximate normal cellular conditions. Interpreting
3S4  Km the impact of enzyme kinetics in living cells is of-
The value for the Michaelis-Menten constant (Km) ten difficult. The conditions necessary to evaluate
is the concentration of substrate [S] required to ob- Vmax require [P] to be zero, which never occurs in
tain an initial velocity (V) that is half the maximal living cells. Thus, enzymes in cells almost never
velocity (Vmax). Km is an indicator of the affinity of could proceed at Vmax. As with other chemical re-
an enzyme for a substrate. A low Km means that actions, the rate and direction of the enzymatic re-

Chemistry, Biochemistry, and Cell Physiology

action depend on the difference between the mass

action ratio, which is calculated from the actual [S]
and [P], and the Keq value, which is the expected
[S] and [P] when the reaction reaches equilibrium.
In a near-equilibrium reaction, the mass action

ratio is close to Keq; the forward and reverse direc-
tions continue at equal rates, with little net change
in [S] or [P]. Most enzyme reactions are far from
equilibrium in cells. If the mass action ratio is
lower than Keq, then the reaction will proceed in
the forward direction. When the mass action ratio
is higher than Keq, the reaction will tend to favor 0 0.1 0.2 0.3 0.4 0.5
the reverse direction. By altering the concentra- [KCI] (M)
tions of substrates and products, cells can regulate (a)
enzyme activities and metabolic pathways.

The physicochemical environment alters

enzyme kinetics
Every enzyme has a characteristic optimal activity
under a specific set of environmental conditions Vmax
(Figure 16). Enzyme kinetics are influenced by envi-
ronmental conditions, such as temperature, pH, salt
concentration, and hydrostatic pressure. While
these factors generally have little impact on your
metabolism, such environmental factors can influ-
ence the metabolic biochemistry of other species.
Some enzymes function optimally under condi- 0 10 20 30 40 50 60
tions that resemble normal cellular conditions. For Temperature (°C)
instance, mammalian enzymes often function opti- (b)
mally at normal body temperatures of 37–40°C.
Figure 16 Effects of salt and temperature on
However, the optimal conditions for many enzymes
enzyme kinetics Most enzymes function optimally under
bear little similarity to normal cellular conditions; physiologically-realistic conditions. (a) The activity of
the optimal temperature for some mammalian en- mammalian enzymes changes in response to the
zymes is well above normal body temperatures. concentration of the salt KCl. Maximal activity occurs at
Environmental conditions typically influence concentrations that approximate those found within the cell
enzyme kinetics through effects on weak bonds. (100–150 mM K). (b) Increasing temperature accelerates
First, changes in weak bonds can alter the three- enzymes. Beyond an optimal temperature, the enzyme
dimensional structure of the enzyme. For in- denatures and loses catalytic activity.
stance, warm temperatures could break bonds
that are necessary to form the active site. Second,
environmental conditions can alter the ionization
proper conformation, but flexible enough to incur
state of critical amino acids within the active site.
conformational changes during catalysis.
For instance, the amino acid histidine is important
Many of the studies assessing the effects of en-
in many active sites, and changes in pH can alter
vironmental conditions have focused on the effects
its protonation state and consequently substrate
of temperature on the enzyme lactate dehydroge-
affinity (Km). Any environmentally induced change
nase (LDH). This enzyme has an important role in
in Km, either an increase or a decrease, can be dis-
glucose metabolism, which we discuss in more de-
ruptive to a cell. Third, environmental conditions
tail later in this chapter. It catalyzes the following
can alter the ability of the enzyme to undergo
reversible reaction:
structural changes necessary for catalysis. En-
zymes must be rigid enough to maintain the Pyruvate  NADH  H Δ lactate  NAD

Chemistry, Biochemistry, and Cell Physiology

Environmental conditions can change the Km petitive inhibitor depends on [S]. When [S] is low,
value of LDH for pyruvate and NADH. Lowering the inhibitor outcompetes S for the active site, re-
temperature increases the affinity of the enzyme ducing the reaction rate. At a very high [S], the in-
for its substrate pyruvate (Figure 17). When com- hibition by the competitor is greatly reduced.
paring the effects of temperature on Km in differ- Thus, a competitive inhibitor increases Km but
ent species, several patterns emerge. First, in doesn’t affect Vmax.
every species, the Km value decreases as tempera- Allosteric regulators are molecules that al-
ture decreases. Second, at any temperature, each ter enzyme kinetics by binding to the protein at lo-
species shows a very different Km value. For exam- cations far away from the active site. The allosteric
ple, when assayed at 15°C, Antarctic fish LDH has regulator alters the three-dimensional structure of
a high Km, LDH from temperate fish has an inter- the enzyme, inducing complex changes in enzyme
mediate Km, and desert lizard LDH has a low Km. kinetics. For example, an allosteric activator could
Third, when the LDH from each species is assayed increase the affinity of the enzyme for the sub-
at its normal body temperature, the resulting Km strate, as depicted in Figure 18b. Allosteric effec-
values fall within a narrow range, from 0.1 to 0.3 tors can activate or inhibit enzyme activity,
mM. Evolutionary variation in LDH structure is re- changing either Km or Vmax. Enzymes often possess
sponsible for the differences between species. multiple sites for different allosteric regulators.
These structural variations provide all the species Enzymes controlled by allosteric regulators are of-
with an enzyme that demonstrates similar kinetics ten larger and more complex than other enzymes.
under their natural conditions. This pattern, Typically, each metabolic pathway is regulated by
called conservation of Km, is common when com- one or more key allosteric enzymes.
paring enzyme kinetics of different animals. Enzymes can also be regulated by the covalent
modification of critical amino acid residues within
the protein. The most common type of covalent
Allosteric and covalent regulation control
modification is protein phosphorylation, where a
enzymatic rates
specific protein kinase transfers the phosphate
Molecules that do not participate directly in catal- group from ATP to an amino acid of the target en-
ysis can also alter enzyme kinetics. Competitive zyme. For instance, tyrosine kinase is a regulatory
inhibitors are molecules that can bind to the ac- enzyme that phosphorylates target proteins at
tive site, preventing substrate molecules from specific tyrosine residues. Another common class
binding (Figure 18a). The effectiveness of a com- of protein kinases is specific for threonine and ser-
ine residues. Protein phosphorylation is reversible.
Cells possess suites of protein phosphatases that
Temperate cleave phosphate groups from phosphorylated
0.5 fish Desert amino acid residues. Phosphorylation might stim-
lizard ulate an enzyme, as depicted in Figure 18c, or in-
0.4 Antarctic fish
Km (mM)

Polar fish
hibit it.

Enzymes convert nutrients to reducing
0 10 20 30 40 50 Enzymes transfer energy from nutrients to mole-
Temperature (°C)
cules that function as energy stores. These energy-
rich molecules are a type of energy currency,
Figure 17 Conservation of Km The Km of an enzyme acting as substrates and products for hundreds of
often changes with temperature. For a number of unrelated
different enzymes. Cells store chemical energy in
species, the Km of LDH for pyruvate (KmPYR) increases with an
two main forms: reducing energy and high-energy
increase in temperature; that is, at warmer temperatures LDH
is less able to bind pyruvate. However, when you examine the
kinetic values that would occur at the actual body temperatures
Many enzymatic reactions capture energy in
for the animal, you find that the Km values are very similar the form of reducing equivalents: NAD and
across species. NADP. The enzymes that use reducing equivalents
(Source: Data from Hochachka and Somero, 2002) are called oxidoreductases and include enzymes

Chemistry, Biochemistry, and Cell Physiology


– Inhibitor
Substrate Inhibitor

+ Inhibitor

– Inhibitor + Inhibitor

Km Km
(a) Competitive inhibition (uninhibited)(inhibited)

+ Activator

Substrate Substrate
bound with bound with – Activator
low affinity high affinity

site Allosteric
– Activator + Activator

Km Km
(b) Allosteric activation (+ Activator) (No activator)

Protein kinase

site OH O P O–

Protein phosphatase
Unphosphorylated Phosphorylated

(c) Covalent activation [S]

Figure 18 Enzyme regulation (a) Competitive In this figure, the allosteric regulator activates the enzyme by
inhibitors are able to bind to the active site of enzymes, increasing the affinity for the substrate, shown in the graph
thereby preventing the real substrate from binding. At low as a decrease in the Km. (c) Many enzymes are controlled by
[S], the inhibitor outcompetes the substrate. However, if [S] is phosphorylation-dephosphorylation. Protein kinases
increased to very high levels, the true substrate outcompetes phosphorylate the target enzyme, transferring a phosphate
the inhibitor, and thus these regulators have no effect on group from ATP to specific hydroxy groups. Protein
Vmax. (b) Allosteric enzymes are regulated by molecules that phosphatases remove the phosphate group. In this figure, the
bind at sites distant from the active site. The resulting enzyme is activated by phosphorylation, greatly increasing
structural change in the enzyme alters its kinetic properties. the Vmax.

Chemistry, Biochemistry, and Cell Physiology

with the common names dehydrogenase, reduc- NH2

tase, and oxidase. When an enzymatic reaction N
transfers an electron to NAD (or NADP), the re- O– O– O–
duced NADH (or NADPH) that is formed can be –O P O P O P O CH2 O N N
used to drive other reactions. In other words, en-
ergy can be stored by reducing a molecule and this O O O H H
energy can be recovered, in part, by oxidizing the
reduced compound. OH OH
Consider the nonenzymatic and enzymatic re- ATP
actions for lactate oxidation. Without an enzyme,
lactate is oxidized to form pyruvate with the fol- COO–
lowing reaction:
O– CH2
Lactate → pyruvate  2H  2e H

G°′  36 kJ/mol O P N C N
O +NH2
The negative standard free energy (G°′)
means that energy is liberated in this reaction,
and without an enzyme the energy released would
be lost as heat. Cells possess the enzyme LDH, in-
troduced earlier in this chapter, which couples lac- O–
tate oxidation to NADH reduction. The NAD H NH3
reduction reaction has a positive G°′. H H H H
NAD  2e  2H → NADH  H O H H H
G°′  62 kJ/mol
–O O
By coupling lactate oxidation to NAD reduc- Phosphoarginine
tion, the enzymatic reaction captures free energy
from lactate oxidation in the form of NADH.
Lactate  NAD → NADH  H  pyruvate
G°′  26 kJ/mol
Note that the enzymatic reaction for lactate
Acetyl CoA
oxidation has a positive G°′, which means the re-
verse direction of this reaction (lactate formation) Figure 19 High-energy molecules Cells
is normally favored. use several energy-rich molecules, such as ATP,
The most important reducing equivalent in en- phosphocreatine, phosphoarginine, and acetyl CoA, as
ergy metabolism is NADH. The reducing energy energy currency.
within the cell, or redox status, is best expressed
as [NADH]/[NAD]. This ratio is high when a cell is less reactions. ATP synthesis requires energy, and
rich in reducing energy, and low when cells are en- ATP breakdown liberates energy.
ergy poor. NAD is a reactant in many enzymes of
ADP3  HPO42  H → ATP4  H2O
energy metabolism, but other enzymes are al-
G°′  30.5 kJ/mol
losterically regulated by NAD. Whether acting
through mass action effects or allosteric regula- ATP possesses two phosphodiester bonds
tion, enzymes sensitive to [NADH]/[NAD] allow (–P–O–P–). Some enzymes break the bond between
metabolic pathways to respond to the energy state. the second and third phosphate groups, forming
ADP. In some cases the inorganic phosphate (Pi) is
released as a product, but often the Pi is trans-
ATP is a carrier of free energy ferred to another molecule. Other enzymes target
Cells use many types of molecules to store energy the bond between the first and second phosphate
(Figure 19), but ATP is the most versatile of these groups, forming AMP and pyrophosphate (PPi).
high-energy molecules and participates in count- Because these energy exchange reactions involve

Chemistry, Biochemistry, and Cell Physiology

a breakdown of a phosphodiester bond, they are of- dine is transferred to ADP to form ATP. In verte-
ten called high-energy bonds. It is important to re- brates, creatine phosphokinase (CPK) catalyzes
alize that the energy is not stored in the bond per this reaction.
se, but is released when ATP hydrolysis occurs—a
Phosphocreatine  ADP Δ ATP  creatine
reaction with large, negative free energy.
The importance of utilizing a metabolite like Acetyl coenzyme A, or acetyl CoA, is another
ATP is, first, to avoid high concentrations of other important high-energy store. Energy is released in
metabolites; participation of ATP permits reac- reactions that hydrolyze its thioester bond
tions that otherwise would be thermodynamically (–O–S–). As we see later in this chapter, many
unfavorable. Second, ATP links major metabolic pathways of biosynthesis and energy metabolism
pathways that require cellular energy, such as en- intersect at acetyl CoA. Collectively, reducing en-
dergonic pathways of biosynthesis, with those that ergy and high-energy compounds provide the en-
generate energy, such as the exergonic process of ergetic support for many cellular processes.
carbohydrate catabolism.
The relative abundance of ATP reflects the en-
ergy status of a cell. The absolute concentration of Proteins
ATP is unimportant; what counts is the relative
Proteins play many important roles in cell struc-
proportion of the adenylate pool (ATP  ADP 
ture and function. Almost all enzymes are proteins
AMP) that exists in the energy-rich forms ATP and
(though many have nonprotein components). Pro-
ADP. The ATP status of the cell is best expressed
teins form the internal skeleton of a cell (cytoskele-
by the phosphorylation potential (Gp), the free
ton) as well the extracellular matrix needed to
energy associated with ATP hydrolysis (ATP →
organize cells into complex tissues. The diversity
ADP  Pi):
in protein structure is afforded by the use of 20
3 ADP 4 3 Pi 4 amino acids that can be strung together in count-
¢Gp  ¢G°¿  RT ln
3ATP 4 less combinations. The blueprint for all proteins in
a cell is in the form of DNA, which is transcribed
ATP is the most common form of energy cur- into RNA and translated to form the appropriate
rency, but the other nucleotides—GTP, TTP, and proteins at the right time.
CTP—have the same energetic value, although
only GTP is commonly used in energy metabolism.
Phosphorylated guanidine derivatives are im-
Proteins are polymers of amino acids
portant energy stores in many animals. Vertebrates Animals build proteins from combinations of 20
use phosphocreatine and invertebrates use phos- amino acids. As the name implies, amino acids
phoarginine, phosphoglycocyamine, phosphotauro- share the general structure of an amino group
cyamine, or phospholombricine. Phosphoguanidine (–NH2) and a carboxylic acid group (–COOH). They
compounds, each with a –P–N– bond, are useful en- are called
-amino acids because both the amino
ergy stores because they do not participate in and carboxyl groups are located on the first, or
many reactions within the cell. Consequently, cells carbon.
can accumulate very high concentrations of phos- Amino acids are distinguished from one an-
phoguanidines without affecting other pathways. other by their side groups (R). The R groups of
The concentration of ATP, in contrast, is kept low polar amino acids form hydrogen bonds with wa-
and relatively constant. Major changes in ATP con- ter. Some polar amino acids are uncharged at
centration would have kinetic consequences for physiological pH values (serine, threonine, cys-
countless enzymes that use ATP as a substrate or teine, tyrosine, asparagines, glutamine), while
product. For instance, the ATP concentration in others possess R groups with side chains that can
vertebrate muscle is typically about 5 mM, become charged. Acidic amino acids (aspartate,
whereas phosphocreatine concentrations might glutamate) are negatively charged at physiological
be 10–50 mM. Animal tissues use these high-energy pH when carboxyl groups become deprotonated
compounds when the need for ATP temporarily (–COOH → –COO  H). Basic amino acids (argi-
outstrips the capacity to produce ATP. When ATP nine, lysine) take on a positive charge when amino
levels decline, the energy within phosphoguani- groups become protonated (–NH2  H → –NH3).

Chemistry, Biochemistry, and Cell Physiology

Many amino acids are nonpolar because their R protein folds onto itself to assume its secondary
groups are aliphatic chains (alanine, valine, structure. The information for proper folding is
leucine, isoleucine, methionine) or aromatic rings contained directly in the primary structure. The
(phenylalanine, tryptophan) that do not readily in- size, charge, and polarity of the side groups influ-
teract with water. The collection of amino acids, ence the interactions between amino acids in the
with their unique properties of side chain length, chain. Secondary structures arise when side groups
shape, charge, and polarity, provides cells with the of amino acids interact to form a structure that is
building blocks necessary to construct thousands more stable than the simple linear conformation.
of different proteins. The two most common protein secondary struc-
tural motifs are the
-helix and the -sheet (Figure
21). In the
-helix, the protein is twisted into a spi-
Proteins are folded into three- ral with 3.6 amino acids per turn and side chains
dimensional shapes extending outward. The structure is stabilized in
Amino acids are polymerized into linear chains by two ways. First, hydrogen bonds form between the
covalent peptide bonds that link the amino group CO of one amino acid and the N–H of the amino
(–NH3) of one amino acid to the carboxyl group acid four positions along the chain. Second, the
(–COOH) of another amino acid.
-helix structure is stabilized when opposing side
chains can interact. With the period of 3.6 amino
acids, a side chain is exposed to the side chain of
| || | ||
the amino acid three or four positions away. For ex-
R1-N-H  H-O-C-R2 → R1-N-C  R2  H2O
ample, if two aromatic amino acids are three posi-
tions apart, when the protein twists into an
the structure will be stabilized by the hydrophobic
Two amino acids in a chain is a dipeptide. interactions between the side chains. Similarly,
Polypeptides are longer chains of amino acids. At negatively charged amino acids are often found
one end of the polymer, called the C terminus, the three residues away from positively charged amino
amino acid has an unbonded carboxyl group. At acids. Their electrostatic interactions stabilize the
the other end, the N terminus, the amino acid has protein. The other common type of secondary
an unbonded amino group. The linear sequence of structure, the -sheet, forms when linear regions of
amino acids in a protein is called the primary a protein align side by side and form hydrogen
structure. bonds. In this conformation, the side chains extend
Once the primary structure is established, above and below the face of the sheet.
proteins are organized into more complex three- Once a protein forms its secondary structure,
dimensional conformations (Figure 20). First, the the different regions fold together to create its


Primary structure Secondary structure Tertiary structure Quaternary structure

Figure 20 Protein structural levels The amino acid sequence of a protein is its
primary structure. This polypeptide can then be folded and organized into three-dimensional

Chemistry, Biochemistry, and Cell Physiology

Disulfide bond Ionic bond

β-Pleated sheet


Figure 21 Protein secondary structure: The ␣-

helix and ␤-sheet The most common secondary
structures in proteins are the
-helix and
-sheet. Weak Hydrophobic interaction Hydrogen bond
bonds stabilize both types of secondary structures. The
information that is used to fold the protein is contained within H H H
the primary sequence.
tertiary structure (Figure 22). If the protein folds N H O=C
in a way that allows two adjacent cysteine H H

residues to come into close proximity, their C C H

sulfhydryl groups (–SH) can form a covalent bond H C
(–S–S–) called a disulfide bond or bridge. Multiple H
weak bonds link various amino acids and side
chains to stabilize three-dimensional structure. Figure 22 Weak bonds and protein tertiary
Many proteins assume a globular structure when structure Both covalent bonds and weak bonds contribute to
hydrophobic interactions form between regions protein three-dimensional structures.
scattered throughout the protein. By pulling to-
gether hydrophobic regions, a hydrophobic core is
formed that stabilizes the structure of the protein. sequence to fold spontaneously, but others require
A protein achieves its quaternary structure the help of molecular chaperones. Each cell con-
when multiple subunits, or polypeptide chains, are tains different types of chaperones to ensure that
brought together. Proteins with two subunits are proteins are properly folded. They work by forcing
called dimers—a homodimer if the monomers the protein into a conformation that allows the ap-
are identical, otherwise a heterodimer. Proteins propriate weak bonds to form.
can be composed of even larger numbers of sub- Environmental conditions, such as tempera-
units, such as trimers (three subunits) and tetramers ture, can alter weak bonds and disrupt three-
(four subunits). dimensional protein structure. Increasing
temperature weakens the hydrogen bonds that
-helices and -sheets. High temperature
Molecular chaperones help proteins fold can cause the protein to unfold, or denature. Once
Proteins can function properly only when they are denatured, a protein can no longer perform its
folded into the correct conformation. Many pro- proper function and may even damage cells.
teins can use the information within the primary Therefore, a partially denatured protein must be

Chemistry, Biochemistry, and Cell Physiology

HOCH2 HOCH2 refolded or destroyed before it can damage the cell.

6 6
5 O 5 O OH Molecular chaperones bind to denatured proteins,
4 1 4 1 folding them into the proper configuration. During
HO 3 2 OH HO 3 2 heat stress, cells increase the levels of molecular
chaperones called heat shock proteins to cope
with the increased number of denatured proteins.
α-D-Glucose (Glc) β-D-Glucose (Glc)

HOCH2 O OH Carbohydrates
OH Carbohydrates share a preponderance of hydroxyl
(–OH), or alcohol, groups, and for this reason they
OH are often called polyols. For any animal, the diet is
a vital source of the carbohydrates used to build
β-D-Galactose (Gal) β-D-Fructose (Fru)
and fuel cells. Glucose, the most common carbohy-
drate in animal diets, is central to cellular energy
HOCH2 HOCH2 metabolism and biosynthesis because of its meta-
O OH O OH bolic versatility. Cells can break glucose down for
energy, or store it for later consumption, or use it
HO HO to build other carbohydrates needed by the cell.

C O Animals use monosaccharides for energy

β-D-Glucosamine (GlcN)
and biosynthesis
N-Acetyl-β-D-glucosamine (GlcNAc) Monosaccharides are small carbohydrates that
Figure 23 Common monosaccharides These have from three to seven carbons. The most com-
structural models of monosaccharides show how side mon monosaccharides are the six-carbon sugars
groups extend above and below the plane of the ring (hexoses) including glucose, fructose, and galac-
structures. The
and forms of glucose differ in the tose (Figure 23). Glucose and galactose, as well as
orientation of the hydroxy group on C-1. mannose, can be modified by the addition of acidic
groups, amino groups, and modified amino
groups. These sugar derivatives serve many pur-
poses in the cell, primarily as modi-
HOCH2 HOCH2 fications of other macromolecules,
HOCH2 O OH O including proteins, lipids, and nu-
1 O
cleic acids.
HO O 4
Many of the sugars that animals
1 β α 1
OH OH obtain in the diet are disaccharides,
OH OH two monosaccharides connected by
OH OH a covalent bond (Figure 24). In or-
Lactose (Gal (β1-4) Glc) Trehalose (Glc (α1-1α) Glc) der to use disaccharides, animals
first break them down into mono-
HOCH2 HOCH2 HOCH2 saccharides. Animals can also pro-
O HOCH2 O O O duce disaccharides such as lactose,
1 α β 2 1 α 4
an important component of milk in
CH2OH O mammalian mammary secretions,
and trehalose, an energy store and
OH OH OH OH solute.
Sucrose (Fru (β2-1α) Glc) Maltose (Glc (1α-α4) Glc) The addition of carbohydrates
Figure 24 Common disaccharides Both trehalose and maltose are made from to other macromolecules is called
two glucose molecules but with bonds forming between different pairs of carbons. glycosylation. Glycosylated lipids
Sucrose and maltose are synthesized in plants; animals obtain them by eating the plants. (glycolipids) and proteins (glyco-

Chemistry, Biochemistry, and Cell Physiology

proteins) are common in the plasma membrane HOCH2 HOCH2 HOCH2 HOCH2
of cells. A glycosylated macromolecule displays an ••• •••
altered molecular profile, changing how it inter- O O O O O

acts with other macromolecules and reducing its OH OH OH OH

susceptibility to degradation. Amylose

Complex carbohydrates perform many ••• •••

functional and structural roles
Complex carbohydrates, or polysaccharides, are
larger polymers of carbohydrates that serve in en-
ergy storage and structure. Polysaccharides can
be composed of long chains of a single type of
monosaccharide or combinations of two alternat-
ing monosaccharides. Common polysaccharides •••

important in metabolism and structure are shown ••• •••

in Figure 25. Starch is a general term for the glu-
cose polysaccharides used by plants and animals
(a) Glucose polymers
for energy storage. Plant starch, a mixture of amy-
lose and amylopectin, is an important dietary HOCH2 HOCH2 HOCH2
source of energy for many animals. Animal starch, O O O
or glycogen, is central to animal energy metabo- O
lism, acting as an internal energy store for most
animals and a nutrient for animals that eat other NH NH NH

animals. Amylose, amylopectin, and glycogen dif- C O C O C O

fer in the linkage between glucose molecules and CH3 CH3

the nature of the branching pattern. Cellulose, an-

other plant-derived glucose polymer, is essentially GlcNAc GlcNAc GlcNAc
indigestible in animals because of the nature of the Chitin
bonds between glucose units. Cellulose, in most HOCH2
animals, provides dietary fiber. However, some
animals, such as ruminants and termites, possess HOCH2 COO –
gastrointestinal symbionts that can degrade cellu- NH
lose for energy. HO
Polysaccharides are also critical structural O NH OH CH3
components of animal cells. Arthropods build C O

their exoskeletons with chitin, a polysaccharide of OH CH3

N-acetyl-glucosamine. Vertebrates secrete hyaluro-

nate, a polymer of N-acetyl-glucosamine and glu- GlcA GlcNAc GlcNAc GlcNAc
curonic acid, into the extracellular space, where Hyaluronate
its gel-like properties act as a spacer between cells (b) Glucose and amino sugar polymers
and tissues. Hyaluronate is a member of a class of
compounds called glycosaminoglycans that in- Figure 25 Polysaccharides (a) Plants and animals
clude chondroitin sulfate and keratan sulfate. use polymers of glucose as energy stores. Amylose and
amylopectin are the two polysaccharides that compose
These compounds are important components of
starch, an important dietary source of energy for animals.
animal tissues, such as cartilage.
Animals produce glycogen, which resembles the plant
In order to use glycogen as an energy store,
polysaccharides but with much greater branching.
animals control the balance between glycogen (b) Animals build many polysaccharides from combinations
synthesis (glycogenesis) and glycogen break- of monosaccharides and amino sugars, such as N-acetyl-
down (glycogenolysis). Glycogen phosphorylase glucosamine (GlcNAc). Chitin is a polymer of N-acetyl-
initiates glycogenolysis, releasing glucose in the glucosamine, whereas hyaluronate is a polymer of
form of glucose 1-phosphate. When glucose is N-acetyl-glucosamine and glucuronic acid (GlcA).

Chemistry, Biochemistry, and Cell Physiology

Glycogen synthase (inactive)

Protein Pyruvate
Protein kinase

Glycogen synthase (active) Pyruvate


Pyruvate carboxylase GTP

Glycogen Glycogen
(n glucose) (n+1 glucose) GDP

Glycogen phosphorylase (active) ATP

Glycogen Glycogen PEPCK

phosphorylase phosphorylase ADP
Malate Phosphoenolpyruvate
kinase phosphatase

Glycogen phosphorylase (inactive) Malate

Figure 26 Control of glycogen synthase and
glycogen phosphorylase Under conditions in which NADH
glycogen breakdown is desirable, both glycogen synthase and
glycogen phosphorylase are phosphorylated by protein CO2
kinases. Phosphorylation inhibits glycogen synthase but
stimulates glycogen phosphorylase. Similarly, PEPCK GTP
dephosphorylation of these two enzymes by protein
phosphatases favors glycogen synthesis.
abundant, glycogen synthase is activated and glu-
cose 1-phosphate is used to increase the size of the 2-Phosphoglycerate
glycogen particle. Protein kinases and protein
phosphatases regulate both glycogen synthase 3-Phosphoglycerate
and glycogen phosphorylase (Figure 26).

Gluconeogenesis builds glucose from 1,3-Bisphosphoglycerate
noncarbohydrate precursors NADH
Glucose is essential for energy metabolism and NAD+
biosynthesis. When dietary glucose is inadequate
or when glycogen stores are compromised, ani-
Glyceraldehyde 3-phosphate Dihydroxyacetone phosphate
mals can produce glucose from noncarbohydrate
precursors via gluconeogenesis. The gluco-
neogenic pathway (Figure 27) using mitochondrial Fructose 1,6-bisphosphate
pyruvate as a starting point has the following over- FBPase
all reaction:
Fructose 6-phosphate
2pyruvate  4ATP  2GTP  2NADH  4H2O →
glucose  4ADP  2GDP  6Pi  2NAD  2H Pi
Glucose 6-phosphate

Figure 27 Gluconeogenesis Cells convert pyruvate Glucose 1-phosphate

to glucose and glycogen using the enzymes of
gluconeogenesis. The exact route of phosphoenolpyruvate
synthesis depends upon tissue and species. Some species UDP
use a mitochondrial PEPCK to produce phosphoenolpyruvate. Glycogen

Chemistry, Biochemistry, and Cell Physiology

Gluconeogenesis begins in the mitochondria, Glucose

where pyruvate carboxylase converts pyruvate to ATP
oxaloacetate, the substrate for PEP carboxykinase
(PEPCK). In species with a mitochondrial PEPCK,
Glucose 6-phosphate Glycogen
PEP is transported to the cytoplasm; if PEPCK is
cytoplasmic, the mitochondria convert oxaloac- Phosphoglucose isomerase
etate to malate, export it, and then resynthesize
Fructose 6-phosphate
oxaloacetate within the cytoplasm. A series of re-
actions produces glucose 6-phosphate, which can ATP
be used to produce glycogen, or in some tissues ADP
converted to glucose by glucose 6-phosphatase.
Fructose bisphosphate
Because gluconeogenesis requires a great deal of
energy, cells stimulate gluconeogenesis only when Aldolase

they have excess energy available. The metabolic

Glyceraldehyde Dihydroxyacetone
indicators of energy status, such as acetyl CoA and 3-phosphate phosphate
adenylates (AMP, ADP, and ATP), regulate the glu-
coneogenic rate. The pathway is controlled mainly
Triosephosphate isomerase
by availability of gluconeogenic substrates and al-
losteric regulation of pyruvate carboxylase and
Glyceraldehyde 3-phosphate 2 NAD+
fructose 1,6-bisphosphatase (FBPase). 2 NADH

1,3-Bisphosphoglycerate (×2)
Glycolysis is a low-efficiency, high-velocity 2 ADP
pathway Phosphoglycerokinase
Glycolysis is the pathway that breaks down glucose 3-Phosphoglycerate (×2)
obtained from the blood and glucose 6-phosphate
derived from processing of the glucose 1-phosphate Phosphoglycerate mutase

liberated from stored glycogen. This pathway is a

2-Phosphoglycerate (×2)
vital source of ATP because it can proceed in the ab-
sence of oxygen (anoxia) and can produce ATP very Enolase
rapidly (albeit for brief periods).
Phosphoenol pyruvate (×2)
Although glycolysis is usually discussed from
the perspective of glucose or glycogen breakdown, 2 ADP
Pyruvate kinase
other carbohydrates derived from the diet are also 2 ATP
processed into hexoses that can enter glycolysis.
Disaccharides are first broken down into mono- Pyruvate (×2)

saccharides: trehalose into two glucose, lactose Figure 28 Glycolysis Glycolysis is a series of
into glucose and galactose, sucrose into glucose cytoplasmic enzymes that breaks down glucose or glycogen
and fructose. The glycolytic pathway (Figure 28) to produce ATP. Because ATP is required by hexokinase,
using glucose as initial substrate has the following glycolysis from glycogen produces more ATP (three ATP per
overall reaction: glucosyl) than it does from glucose (two ATP per glucose).
The other important products of glycolysis are pyruvate and
Glucose  2ADP  2NAD →
NADH. The three irreversible reactions are highlighted.
2ATP  2pyruvate  2NADH  2H
When glucose is carried into the cell, the enzyme Seven of the ten glycolytic reactions are freely re-
hexokinase rapidly phosphorylates it, using a mole- versible, and catalyzed by the enzymes shared with
cule of ATP. Since glucose 6-phosphate is not the gluconeogenic pathway. The three irreversible
readily transported across the cell membrane, glycolytic reactions—hexokinase, phosphofructoki-
phosphorylation of glucose traps glucose within the nase (PFK), and pyruvate kinase (PK)—are impor-
cell. The next steps in glycolysis are a series of enzy- tant sites of regulation for the pathway, acting via
matic reactions that convert the glucose backbone mass action effects, allosteric regulation, and cova-
to fructose, which is then hydrolyzed to form two lent modification. During periods of high energy de-
trioses that are ultimately converted to pyruvate. mand, much of the ATP is broken down to ADP and

Chemistry, Biochemistry, and Cell Physiology

AMP, affecting the mass action ratios for all three pyruvate dehydrogenase (PDH) produces acetyl
regulatory enzymes. Both ADP and AMP are power- CoA, which is further oxidized to produce CO2. The
ful activators of PFK enzymatic activity, whereas reducing energy (4 NADH and 1 FADH2) and nu-
ATP inhibits PFK, as well as PK. When cells do not cleotides (1 GTP) allow mitochondria to produce
need energy, glycolysis is inhibited at PFK and PK. the equivalent of 15 ATP from pyruvate. Since the
With PFK inhibited, glucose 6-phosphate is diverted cytoplasmic production of pyruvate produces only
into glycogen synthesis. Thus, the fate of the glucose 1 ATP per pyruvate, considerably more energy is
6-phosphate—glycolysis or glycogen synthesis—is produced by glucose oxidation (glucose → CO2)
linked to energy status through regulation of PFK. than by glycolysis (glucose → pyruvate).
This is an example of negative feedback regulation, Mitochondria also dispose of the cytoplasmic
where an increase in the concentration of products NADH produced in glycolysis. Although they cannot
inhibits the pathway. oxidize NADH directly, mitochondria use two
In addition to the 2 mol of ATP per glucose, gly- redox shuttles to obtain the reducing energy of cy-
colysis produces 2 mol of pyruvate and NADH. Gly- toplasmic NADH: the
-glycerophosphate shuttle
colysis can continue only if the cell can remove the and the malate-aspartate shuttle (Figure 29). In the
pyruvate and NADH produced. The fate of these
-glycerophosphate shuttle, cytoplasmic NADH is
products depends on two factors: the metabolic de- first oxidized by the enzyme
mands of the cell and the availability of oxygen. dehydrogenase (
-GPDH), embedded within the
mitochondrial inner membrane. Oxidation of gly-
colytic NADH in the
-glycerophosphate shuttle
Mitochondria oxidize glycolytic pyruvate generates two ATP. The malate-aspartate shuttle
and NADH under aerobic conditions uses pairs of enzymes that are located in both the
When energy is required and oxygen abundant, cytoplasm and the mitochondria. First, cytoplasmic
pyrvuate produced in glycolysis enters the mito- malate dehydrogenase oxidizes NADH. This trans-
chondria for further oxidation. First, the enzyme fers the reducing energy of NADH to malate, which

Glycolysis Oxaloacetate
Glucose Pyruvate
6 1

2-Oxoglutarate Glutamate
NAD+ NADH + H+ Aspartate Malate

Inner membrane
5 2

Cytosol FAD+ FADH2 Aspartate 2-Oxoglutarate Glutamate
Inner membrane Q 3
– 4
Matrix AspAT NADH

(a) α Glycerophosphate shuttle (b) Malate-aspartate shuttle

Figure 29 Redox shuttles (a) Glycolytic NADH can mitochondria with complete cycling of the reactants. The
be oxidized by the combined actions of cytoplasmic and enzymes malate dehydrogenase (MDH) and aspartate
mitochondrial forms of glycerol 3-phosphate dehydrogenase. aminotransferase (AspAT) are located in both the cytoplasm
The complete
-glycerophosphate shuttle leads to transfer of and mitochondria. This cycle also requires specific
the reducing power of NADH to mitochondrial FADH2. (b) The transporters capable of carrying metabolites across the
malate-aspartate shuttle, shown as a series of reactions mitochondrial membrane.
from 1 to 6, results in net transfer of NADH into the

Chemistry, Biochemistry, and Cell Physiology

enters the mitochondria and is oxidized by malate demands of specific tissues. For example, a turtle
dehydrogenase. The remainder of the cycle ensures can depress its metabolic rate at the onset of a dive.
that the cytoplasm is provided with adequate ox- Second, animals can extend hypoxic survival by
aloacetate and the mitochondrial oxaloacetate is re- storing high levels of glycogen. For some bivalve
moved. The enzyme aspartate aminotransferase molluscs, for example, almost half their dry weight
converts oxaloacetate to aspartate in the mitochon- is glycogen, providing many days of anoxia toler-
dria. Aspartate is exported to the cytoplasm where ance. Third, some anoxia-tolerant organisms alter
another aspartate aminotransferase regenerates the nature of glycolysis to produce an alternative
oxaloacetate. The other substrates and products in end product that is less toxic than lactate. Some
the aspartate aminotransferase reaction, glutamate molluscs produce strombine, alanopine, or oc-
and 2-oxoglutarate, are required in the transport of topine. Some species of fish can convert lactate to
malate and aspartate. ethanol, which is then excreted into the water. This
additional reaction spares them the toxicity of lac-
Terminal dehydrogenases oxidize NADH tate, but in the process they lose a valuable source
under anaerobic conditions of energy. Bivalve molluscs and some endoparasites
Since mitochondria require oxygen to process also produce alternate end products, but gain extra
pyruvate and NADH, the nature of the end prod- energy along the way. Phosphoenolpyruvate (PEP)
ucts of glycolysis depends on the availability of can be diverted from glycolysis to produce succinate
oxygen. Environmental hypoxia arises when ex- (4 ATP/glucose) or propionate (6 ATP/glucose).
ternal oxygen levels fall below critical levels for The various alternative pathways and anaerobic
prolonged periods. Intertidal bivalves may close end products are summarized in Figure 30. Col-
their shells during tidal cycles, inducing hours of Glucose
hypoxia, whereas parasites of the gastrointestinal
tract live perpetually under hypoxia. Functional
anoxia can arise when tissue oxygen demands NADH
outstrip oxygen delivery from the blood. For ex- Pyruvate

ample, muscle can become hypoxic during intense

exercise. Diving animals gradually deplete their NADH
onboard oxygen stores, causing short-term hy-
Ethanol Lactate
poxia in some tissues. In each of these situations,
animals depend on glycolysis for energy and must Oxaloacetate Tauropine (x=taurine)
be able to oxidize NADH to allow glycolysis to con- Nopaline (proline)
NADH Alanopine (alanine)
tinue. One of the most common pathways for Strombine (glycine)
NAD regeneration is through the activity of LDH, Lysopine (lysine)
Octopine (arginine)
an enzyme we introduced earlier in this chapter. Malate
Pyruvate  NADH  H Δ lactate  NAD
This reaction regenerates NAD and disposes of
pyruvate, permitting glycolysis to continue. For Fumarate

many species, lactate production is a good indica-

tion of glycolytic flux. Once produced in the LDH
reaction, lactate can either be retained in the tis-
sue or exported from the cell into extracellular
fluid. Although lactate is slightly toxic, it can be tol-
erated for short periods. When the anoxia bout
ends, lactate is metabolized, and is often used as a Propionate
substrate to regenerate glucose and glycogen.
Figure 30 Anaerobic end products of glycolysis
The most hypoxia-tolerant and anoxia-tolerant Animals collectively have many different ways to oxidize
animals use three general mechanisms to extend NADH when oxygen is limiting. Many animals and tissues rely
survival. One is to reduce their metabolic demands on lactate dehydrogenase, but other pathways occur in
to extend the life of their energy stores by entering hypoxia-tolerant animals. Some anaerobic end products can
some form of dormancy or reducing the metabolic lead to production of extra ATP.

Chemistry, Biochemistry, and Cell Physiology

lectively, these variations of glycolysis allow ani- Medium chain fatty acids (MCFAs) and long chain
mals to succeed in anoxic environments that are fatty acids (LCFAs) are common in energy stores
toxic to other species. and as part of phospholipids that make up cell
membranes. Fatty acids also differ in the number
and position of double bonds between carbon
Lipids atoms. Saturated fatty acids have no double bonds
and are linear in structure. The introduction of a
Lipids are a class of hydrophobic organic mole-
double bond into a linear fatty acid causes a bend
cules including fatty acids, triglycerides, phospho-
in the chain, which has important consequences
lipids, steroids, and steroid derivatives. They have
for membrane structure. Monounsaturated fatty
many roles in animal cells, acting as substrates for
acids have one double bond. Polyunsaturated fatty
energy production, building blocks for mem-
acids, or PUFAs, possess multiple double bonds.
branes, and signaling molecules.
Fatty acid nomenclature considers both the
chain length and the number of bonds. Palmitic
Fatty acids are long aliphatic chains acid is denoted as 16:0, meaning it is 16 carbons
produced from acetyl CoA long and has no double bonds. There are two
Fatty acids are long chains of carbon atoms naming systems to denote fatty acids, which differ
(aliphatic) ending with a carboxyl group (Figure in how they identify the location of the first double
31). They can vary in chain length from two car- bond. In the delta () system, a number corre-
bons, as with acetate, to more than 30 carbons. sponds to location of the double bond relative to
The shortest fatty acids are often called volatile the carboxyl carbon; in the omega (ω) system, the
fatty acids, or VFAs, because they readily evapo- number refers to the distance from the methyl end
rate from solution. VFAs are produced by rumi- of the fatty acid. Thus, the 18-carbon fatty acid
nants with the bacterial fermentation of cellulose. oleic acid can be either 18:1 9 or 18:1 ω9. Linoleic
acid is denoted as either 18:2 9,12 or 18:2 ω6.
Animals can produce many fatty acids using
2 4 6 8 10 12 14 16 18
O C C C C C C C C C the enzyme fatty acid synthase, which cyclically
adds two-carbon units to the fatty acid. Though
1 3 5 7 9 11 13 15 17 fatty acids grow by adding acetyl groups, malonyl
CoA, a three-carbon activated fatty acid is the ac-
18:0 - Stearic acid (saturated) tual substrate for the enzyme fatty acid synthase.
C Malonyl CoA is produced by acetyl CoA carboxy-
C lase. Using the reducing energy of NADPH, fatty
O C C C C C acid synthase repeatedly adds acetyl CoA groups
C C C C C C to the fatty acid. After seven cycles, when the fatty
acid has grown to 16 carbons, palmitate has been
produced and is released by the enzyme. The
18:1 (Δ9) - Oleic acid (monounsaturated) overall reaction for palmitate synthesis is

Acetyl CoA  7malonyl CoA  7NADPH 
C 7H → palmitate  7NADP
C C C C C C Though palmitate is the product of fatty acid
C synthase, accessory enzymes process much of it to
produce other fatty acids. These enzymes elongate
the carbon chain and introduce double bonds to
18:2 (Δ9,12) - Linoleic acid (polyunsaturated) produce the other important fatty acids, such as
oleic acid. Many animals can produce all of the
Figure 31 Fatty acids Saturated fats such as stearic
acid (18:0) are linear in structure. Addition of a double bond, fatty acids needed for growth, but some animals
as shown with the monounsaturated fatty acid oleic acid are incapable of producing specific fatty acids and
(18:1), introduces a bend in the structure. The second double must obtain these in the diet. For example, hu-
bond shown in the polyunsaturated acid linoleic acid (18:2) mans have a dietary requirement for linoleic acid
causes further disruption of the linear structure. (18:2 ω6) and linolenic acid (18:3 ω3).

Chemistry, Biochemistry, and Cell Physiology

Fatty acids are oxidized in mitochondrial H H H

-oxidation C C C C
Fatty acids are an important fuel for many tissues, O–
such as the mammalian heart, which typically de- Fatty acid
rives more than 70% of its energy from fatty acid
oxidation. The fatty acid oxidation pathway occurs ATP
Activation Fatty acyl CoA synthase
primarily in the mitochondria and results in the CoASH
production of acetyl CoA. Depending on the condi- AMP+PPi
tions, this acetyl CoA can be oxidized by mitochon-
dria or be diverted to other pathways. Fatty acids O
can have many structures, differing in chain length, C C C C
branching patterns, and desaturation. These varia- S-CoA
tions require side reactions to convert the fatty Fatty acyl CoA
acids to forms that can enter -oxidation. We will
focus on the pathway for oxidation of palmitate, but Oxidation Fatty acyl CoA dehydrogenase FAD
along the way we will identify some of the alternate
pathways used to process other fatty acids. H H H
Because the actual substrate for -oxidation is C C C C
fatty acyl CoA, cells must first convert fatty acids to S-CoA
their CoA esters using a fatty acyl CoA synthase. H
Enoyl CoA
Short and medium chain fatty acids are able to en-
ter the mitochondria directly, where they are acti- H2O
Hydration Enoyl CoA hydratase
vated by a mitochondrial fatty acyl CoA synthase.
Palmitate, which cannot cross into mitochondria,
is oxidized by the mitochondria by a multistep O
process involving activation and transport. The C C C C
fatty acid is converted to fatty acyl CoA. Next, the S-CoA
enzyme carnitine palmitoyl transferase-1, or CPT-1, β-Hydroxyacyl CoA
replaces the CoA with carnitine, forming fatty acyl NAD+
carnitine, which is carried into the mitochondria, Oxidation β-hydroxyacyl dehydrogenase
where another enzyme, CPT-2, converts it back to NADH +H+
fatty acyl CoA. This elaborate transport scheme
provides an extra level of control over long chain O
fatty acid oxidation. By regulating the activity of C C C C
CPT-1, cells control how much fatty acid can enter H H
the mitochondria for catabolism. β-Ketoacyl CoA
Once inside the mitochondria, fatty acids enter
the -oxidation pathway (Figure 32). This is a Thiolysis Thiolase
cyclical pathway that sequentially cuts pairs of
carbons off the end of the fatty acid in the form of H H
acetyl CoA. The shortened fatty acid returns to the
C C + HC C
pathway, and the cycle is repeated until the entire
fatty acid is broken down to acetyl CoA. With each H H
trip through the pathway, reducing equivalents are Fatty acyl CoA Acetyl CoA
produced at two enzymatic steps: fatty acyl CoA de- Figure 32 Fatty acid oxidation Fatty acids are
hydrogenase produces FADH2, and -hydroxyacyl activated in the cytoplasm to form fatty acyl CoA. Once
CoA dehydrogenase produces NADH. About 30% of transported into mitochondria, fatty acyl CoA enters the
the energy liberated from fatty acids is derived from -oxidation pathway. Oxidation, hydration, oxidation, and
the reducing equivalents produced in -oxidation. thiolysis produce acetyl CoA, reducing equivalents, and a fatty
The remaining 70% derives from oxidation of acetyl acyl CoA shortened by two carbons. The shortened fatty acyl
CoA in the TCA cycle. CoA reenters the -oxidation pathway and the cycle repeats
until the fatty acid is reduced to acetyl CoA units.

Chemistry, Biochemistry, and Cell Physiology

Ketogenesis Ketolysis
tivated into the CoA ester, then hy-
drolyzed by thiolase to form two
2 Acetyl CoA 2 Acetyl CoA acetyl CoA molecules.
Ketone bodies are a useful alter-
Thiolase CoASH CoASH Thiolase native to fatty acids for many ani-
Acetoacetyl CoA Acetoacetyl CoA mals. Although some energy is lost in
Acetyl CoA the complete cycle of ketogenesis and
synthase Succinate ketolysis, for some tissues, particu-
β-Ketoacyl larly under starvation conditions, ke-
HMG-CoA Succinyl
CoA CoA tone bodies are the only metabolic
synthase transferase
HMG CoA energy source available. Chon-
lyase Acetyl CoA drichthians (sharks and their rela-
Succinyl CoA
Acetoacetate Acetoacetate tives) in fact appear biochemically
NADH + H+ NADH + H+ predisposed to using ketone bodies
β-HBDH β-HBDH as their “lipid” fuel. Unlike in other
vertebrates, their muscles are unable
β-Hydroxybutyrate β-Hydroxybutyrate
to use fatty acids directly, instead re-
lying on ketone bodies as a fuel for
Figure 33 Ketone metabolism Acetyl CoA can be converted to the ketone
bodies acetoacetate and -hydroxybutyrate. This reaction normally occurs in specific energy.
ketogenic tissues, such as liver. Ketone bodies are released through the blood for
uptake by ketolytic tissues, such as brain. Acetyl CoA is resynthesized at the cost of
Triglyceride is the major form
one GTP to regenerate the substrate succinyl CoA.
of lipid storage
Most fatty acids in animal cells are es-
Fatty acids can be converted to ketone terified to a glycerol backbone. A monoacylglyceride
bodies has a single fatty acid esterified to glycerol, typically
Fatty acids are valuable sources of energy, but un- at the first position of the glycerol molecule. Diacyl-
der some conditions they must first be processed glyceride has fatty acids esterified to the first and
into ketone bodies: acetone, acetoacetate, and second position of glycerol. Triglyceride has three
-hydroxybutyrate (Figure 33). Ketone bodies fatty acids esterified to the glycerol backbone (Fig-
provide a fuel for tissues that cannot use fatty ure 34). Each of these terms—monoacylglycerides,
acids directly. The mammalian brain usually re- diacylglycerides, and triglycerides—refers to a class
lies on glucose oxidation for energy, but after an of molecules. For example, hundreds of chemically
extended period of food deprivation, glucose lev- distinct triglyceride molecules can be constructed by
els may decline, forcing tissues to rely more on using different fatty acids in each of the three posi-
lipid stores. Since the brain cannot use fatty acids tions on the glycerol backbone.
directly, the liver converts the fatty acids to ketone
bodies, which can be transported into the brain H H H
and oxidized.
H C C C H Glycerol
The first step in ketone body synthesis, or ke-
togenesis, is the production of acetoacetyl CoA O O O
from two molecules of acetyl CoA, catalyzed by thi-
olase. This is the same enzyme used in the final step
of -oxidation, but in ketogenesis it operates in the CH2 CH2 CH2

reverse direction. After condensation with another Fatty acids

acetyl CoA and subsequent hydrolysis, acetoacetate



is formed. Acetoacetate can then be converted to CH3 CH3 CH3

-hydroxybutyrate by the enzyme -hydroxybu-
tyrate dehydrogenase ( -HBDH), or it can break Figure 34 Triglycerides Triglycerides are composed
down spontaneously to form acetone. In the target of three fatty acids esterified to a glycerol backbone. Fatty
tissues, ketolysis reconverts -hydroxybutyrate acids can vary in chain length and number
and acetoacetate to acetyl CoA. Acetoacetate is ac- of double bonds.

Chemistry, Biochemistry, and Cell Physiology

Triglycerides are vital energy stores for ani- Dihydroxyacetone

mals, and can be found in high concentrations in phosphate Glycerol

lipid storage tissues in the form of lipid droplets. In

insects, a tissue called the fat body is the main site
of lipid storage. Many other invertebrates, such as
molluscs and crustaceans, store lipid in a large he-
patopancreas. Vertebrates store triglyceride in CoASH Glycerol–3–P

liver, muscle, and adipose tissue, such as blubber.

Adipocytes, the cells within adipose tissue, store

Fatty acid

Fatty acid
triglyceride when an animal is well fed, then release
lipids when the animal needs extra fuel.
Triglyceride synthesis, or lipogenesis, is a
multistep process overlapping with phospholipid
synthesis (Figure 35). Each fatty acid is activated
into its CoA ester by fatty acyl CoA synthase. Start- Pi
ing with glycerol 3-phosphate, the fatty acids are
added sequentially to carbon 1, then carbon 2,
forming a phosphatide. After removal of the phos-
phate group, diacylglycerol is formed. Addition of a Phosphatidic Phospholipid
acid synthesis
third fatty acid completes the triglyceride molecule.
Triglyceride breakdown, or lipolysis, requires
enzymes called lipases that attack the triglyceride
molecule, breaking the bond between the fatty acid
and the glycerol backbone. Hormone-sensitive li-
pase liberates fatty acids from triglycerides and di-
acylglycerides. Another lipase, monocyglyceride
lipase, completes the breakdown of the triglyceride Diacylglycerol
by releasing the last fatty acid from the glycerol
backbone. The liberated fatty acids are either used CoASH
directly within the cell or transferred to the circula-
tion for uptake by other tissues that use them for
energy metabolism.
The balance between triglyceride synthesis
and degradation is carefully controlled within an-
imals. Lipolysis does not directly generate energy,
but lipogenesis requires energy. As with other Figure 35 Triglyceride synthesis Glycerol
pathways we have discussed, if both synthesis and 3-phosphate, produced from glycolysis (dihydroxyacetone
phosphate) or glycerol, is the acceptor for two sequential
degradation occurred simultaneously, cells would
additions of activated fatty acids (fatty acyl CoA). The
waste energy.
formation of triglyceride requires dephosphorylation and
addition of another fatty acid group to the third and last
Phospholipids predominate in biological position on the glycerol backbone.
In addition to their role in energy metabolism, fatty group, such as serine, choline, ethanolamine, and
acids are vital components of the phospholipids inositol. The physical properties of a phosphoglyc-
used to produce biological membranes. Animal eride are determined by the properties of both the
cells produce two classes of phospholipids: phos- fatty acids (chain length, saturation) and the polar
phoglycerides and sphingolipids (Figure 36). head group.
Phosphoglycerides are constructed from Although sphingolipids are chemically very
phosphatides, an intermediate in triglyceride syn- different from phosphoglycerides, they have simi-
thesis. In phospholgylceride synthesis, the phos- lar three-dimensional shapes. The backbone of a
phate group links the phosphatide to a polar head sphingolipid is sphingosine. With its long aliphatic

Chemistry, Biochemistry, and Cell Physiology

+ makes a specific combination of sphingolipids,
providing a kind of cellular signature that other
cells can recognize. During development, when
cells move throughout the body to begin the
process of tissue formation, sphingolipid signa-

tures provide migrating cells with landmarks.
When the migrating cells find the correct sphin-
Glycerol golipid signature, they cease migration and differ-
entiate to form tissues.
Phospholipids are broken down by phospho-
lipases, many of which are important in cell
Fatty acid

Fatty acid

signaling cascades. Each type of phospholipase at-

tacks a specific region of a phospholipid molecule.
Phospholipase A (PLA) breaks the ester bonds that
connect the fatty acids to the glycerol backbone.
PLA1 releases the fatty acid from the first carbon
(a) Phosphoglycerides of glycerol, whereas PLA2 releases the fatty acid
from the second position. Phospholipases B and C
break different phosphodiester bonds between the
+ polar head group and the glycerol backbone.

When PLB attacks phosphatidyl inositol, inositol
and phosphatide are produced. When PLC attacks
the same phospholipid, inositol phosphate and di-
acylglyceride are released. It is an important en-
zyme in signal transduction pathways of many
Fatty acid

Steroids share a multiple ring structure

Steroids are a collection of lipid molecules that
share a basic aromatic structure of four hydrocar-
bon rings. The steroid cholesterol is found in
many cellular membranes and is part of the
lipoprotein complexes that transport lipids
(b) Sphingolipids through the blood. It is also a precursor for syn-
Figure 36 Phospholipids Phospholipids, including thesis of the vertebrate steroid hormones. Al-
(a) phosphoglycerides and (b) sphingolipids, share a similar though invertebrates don’t possess steroid
three-dimensional structure. They are built on different hormones, some use a steroid-like hormone,
backbones: glycerol for phosphoglycerides and sphingosine ecdysone, to control maturation and development.
for sphingolipids. The pathways of steroid synthesis involve
nonsteroid intermediates (Figure 37). Steroid syn-
chain, its structure is similar to monoacylglycerol. thesis begins when acetate is used to produce
Ceramide is formed when a fatty acid is esterified mevalonate, the precursor for activated isoprene.
to sphingosine, creating a structure that resem- Activated isoprene is the precursor for many fa-
bles diacylglycerol. Many different types of sphin- miliar molecules, such as carotenoids and vita-
golipid can be constructed by attaching different mins A, E, and K. Ubiquinone, a type of quinone,
polar head groups to ceramide. When phospho- is an important component in mitochondrial en-
choline is attached to ceramide, sphingomyelin is ergy production. Activated isoprene is also used to
formed. Carbohydrates can be attached to ce- produce isoprenoids that act as hormones, includ-
ramide to form neutral glycolipids and ganglio- ing insect juvenile hormone and pheromones.
sides. Sphingolipids are most often found on the Further along the pathway of cholesterol synthesis
extracellular side of the cell membrane. Each cell

Chemistry, Biochemistry, and Cell Physiology

is squalene, a steroid used by sharks to aid in Acetate

buoyancy. Cholesterol is the precursor for many
steroid hormones.
Vitamin K Mevalonate Vitamin A

Mitochondrial Metabolism
Ubiquinone Activated isoprene Carotenoids
Mitochondria process metabolites generated in
the cytoplasm, breaking them down to capture
their chemical energy in the form of ATP. The main Isoprenoids Squalene Vitamin E
point of entry for mitochondrial energy-producing
pathways is acetyl CoA, which as you’ve learned
earlier is produced in many pathways (Figure 38). Vitamin D Cholesterol Bile acids
Acetyl CoA enters the cyclical tricarboxylic acid
cycle (TCA cycle) and is oxidized to form reduc-
ing equivalents (NADH, FADH2), which provide the Pregnenolone
fuel for mitochondrial ATP production.

Corticosterone Progesterone Testosterone

The TCA cycle uses acetyl CoA to generate
reducing equivalents
Aldosterone Cortisol Estradiol
Once acetyl CoA is produced within mitochondria,
its fate depends on intracellular conditions. When Figure 37 Steroid biosynthesis This simplified pathway
cells need energy, acetyl CoA enters the TCA cycle, of steroid synthesis illustrates the many intermediates that are
where its oxidation ultimately leads to ATP pro- used by cells.
duction. The TCA cycle (Figure 39) consists of
eight enzymes that collectively catalyze the follow- enzymes, and the catalytic activity of enzymes.
ing reaction: Tissues that use a lot of energy, such as heart and
brain, have high levels of the TCA enzymes. In
Acetyl CoA ! 3NAD! ! GDP ! Pi ! FAD ’
many tissues, the flux through the TCA cycle is af-
2CO2 ! 3NADH ! FADH2 ! GTP
fected by the levels of acetyl CoA and oxaloacetate,
The four dehydrogenases in the TCA cycle pro- as well as other intermediates in the cycle. When
duce reducing equivalents: NADH is produced by tissues have abundant energy, they typically use
isocitrate dehydrogenase, 2-oxoglutarate dehy- acetyl CoA and intermediates as biosynthetic sub-
drogenase, and malate dehydrogenase; FADH2 is strates. Acetyl CoA is an important substrate in
produced by succinate dehydrogenase. Most of the fatty acid synthesis, and oxaloacetate is a sub-
ATP produced through acetyl CoA oxidation comes strate for glucose synthesis. When biosynthetic re-
from the subsequent oxidation of NADH and actions deplete these substrates, the rate of the
FADH2. The TCA cycle also produces one molecule TCA cycle declines. Allosteric effectors also regu-
of GTP, which is energetically equivalent to ATP. late the TCA cycle. Calcium, frequently elevated
This reaction, catalyzed by succinyl CoA synthase,
is an example of substrate-level phosphoryla-
Dietary sucrose Glucose Dietary starch
tion. The TCA cycle is not really an isolated path-
way so much as a collection of enzymes acting on
a pool of metabolites exchanged with other path-
ways. When intermediates are removed for other Lactate Pyruvate Amino acids
reactions, cells use anaplerotic pathways to re-
Fatty acids Amino acids
generate the intermediates. Ketone bodies
Cells control the rate of the TCA cycle in three
ways: by regulating the concentrations of reac-
Acetyl CoA
tants (substrates and products), the levels of the
Figure 38 Acetyl CoA production from diverse

Chemistry, Biochemistry, and Cell Physiology

Acetyl CoA pass electrons directly to ubiquinone.

For example, the TCA cycle enzyme
Citrate synthase
succinate dehydrogenase is actually
Oxaloacetate Citrate complex II of the ETS. An FAD group
within its structure becomes reduced
dehydrogenase NADH Aconitase during oxidation of succinate, form-
ing FADH2. The enzyme in turn
passes the electrons from FADH2 to
Malate Isocitrate ubiquinone. Once reduced, ubiquin-
one transfers its electrons to com-
plex III, which in turn transfers
Fumarase Isocitrate electrons to cytochrome c. Complex
dehydrogenase IV, or cytochrome c oxidase, ac-
cepts electrons from cytochrome c
and passes them on to molecular
Fumarate 2-Oxoglutarate oxygen. Complete reduction of oxy-
FADH2 NADH gen (O2) requires four electrons
Succinate 2 -Oxoglutarate
CO2 from cytochrome c and consumes
dehydrogenase dehydrogenase
four protons to produce two water
Succinate Succinyl CoA molecules.
Complexes I, III, and IV are also
Succinyl CoA proton pumps. When these com-
plexes transfer energy to the next
Figure 39 Tricarboxylic acid cycle The enzymes of the TCA cycle oxidize carrier, enough free energy remains
acetyl CoA to release its energy in the form of reducing equivalents (3 NADH, 1 FADH2) to pump protons out of the mito-
and 1 GTP. chondrial matrix. Fewer protons
are pumped in the oxidation of
during periods of high metabolic demand, stimu- FADH2 because these enzymes pass their electrons
lates isocitrate dehydrogenase and 2-oxoglutarate directly to ubiquinone, bypassing the proton-
dehydrogenase, increasing the rate of NADH pro- pumping complex I. The proton gradient formed
duction to help the cell meet its energy demands. by the ETS has both electrical and chemical com-
ponents: a pH gradient (pH) and a membrane po-
tential (Ψ). This proton motive force is potential
The ETS generates a proton gradient, heat, energy that can be used to drive other processes,
and reactive oxygen species such as ATP synthesis.
Mitochondria use reducing equivalents as the sub- The ETS converts much of the energy liber-
strate for oxidative phosphorylation, a complex ated from NADH oxidation to the proton motive
pathway that combines oxidation by the electron force. Some energy is “lost” in the formation of two
transport system (ETS) with phosphorylation by-products: heat and reactive oxygen species
(Figure 40). The ETS builds an electrochemical (ROS). Conditions that increase electron flow and
gradient that can be used to drive ATP synthesis oxygen consumption also increase heat produc-
and energy-dependent transport processes. tion. ROS production is an inevitable consequence
Found within the inner mitochondrial membrane, of electron movement throught the ETS. Usually
the ETS consists of four multisubunit proteins more than 99% of the electrons that enter the ETS
(complexes I, II, III, and IV) and two electron car- make the journey all the way to the end of the
riers (ubiquinone, cytochrome c). chain, forming water. However, a few are stolen
Although electrons can enter the ETS in several from the ETS by molecular oxygen to form super-
ways, each pathway converges on the first mobile oxide (O2), a potent ROS that can attack chemical
carrier, ubiquinone. The NADH produced in the bonds, damaging macromolecules such as lipids,
TCA cycle passes electrons to complex I, which in proteins, and DNA. Cells possess vigorous antiox-
turn reduces ubiquinone. Several FADH2-linked en- idant defense mechanisms to inactivate superox-
zymes found in the inner mitochondrial membrane ide before it can cause damage. The enzyme

Chemistry, Biochemistry, and Cell Physiology

Electron transport system Phosphorylation

H+ H+ H+ space
Electron C

Complex Complex Complex Complex

inner membrane
Complex II


+ H+
H+ H + H+
Succinate H 2O
NAD+ Fumarate
+ Pi
H+ matrix

Figure 40 Oxidative phosphorylation Complex I (Q). Electron transfer continues through complex III,
collects electrons from NADH produced by various cytochrome c, and finally complex IV, cytochrome oxidase.
mitochondrial dehydrogenases. Complex II, or succinate During electron transport, complexes I, III, and IV also pump
dehydrogenase, transfers electrons from succinate to FAD. protons out of the mitochondrial matrix, creating the proton
Both complex I and II, as well as other FAD-link motive force (p). The mitochondrial F1FO ATPase (complex V)
dehydrogenases not shown, transfer electrons to ubiquinone uses p to fuel ATP synthesis.

superoxide dismutase, or SOD, consumes super- ylation; the two processes are functionally coupled
oxide to produce hydrogen peroxide (H2O2), which through a mutual dependence on p.
is less toxic than superoxide. Other antioxidant en- The rate of ATP synthesis by the F1FO ATPase
zymes, such as catalase and glutathione peroxi- depends on the magnitude of p and the availabil-
dase, consume H2O2, preventing it from causing ity of the substrates ADP and inorganic phosphate
cellular damage. (Pi). When cells are rapidly hydrolyzing ATP, [ADP]
and [Pi] increase, accelerating the rate of the F1FO
ATPase reaction. To understand how this process
The F1FO ATPase uses the proton motive is regulated, consider what happens in a muscle
force to generate ATP that goes from rest to exercise. At rest, the rate of
To this point we have discussed how mitochondria ATP breakdown is slow and [ATP] builds up while
build p but not how it is used to produce ATP. Mi- [ADP] and [Pi] decline. The ETS builds p to its
tochondria possess an ATP synthase, usually maximum because the ATPase, the major drain on
called the F1FO ATPase, that uses the energy con- the gradient, is inhibited. With little flux through
tained in p to drive the phosphorylation of ADP. the ETS, the rate of respiration is low. This is the
(Although it normally functions in the direction of biochemical reason why you breathe less when
ATP synthesis, the F1FO ATPase is reversible and resting. When muscle activity begins, ATP is hy-
able to break down ATP under some conditions.) drolyzed and the concentrations of ADP and Pi in-
The F1FO ATPase possesses a proton-pumping re- crease. With the stimulation of the ATP synthase,
gion and a catalytic region. When protons pass p is depleted and ETS accelerates to replenish
through the enzyme, which spans the mitochon- the gradient. We increase our oxygen consump-
drial inner membrane, the energy is used to catalyze tion during exercise because of this linkage be-
the synthesis of ATP. Oxidative phosphorylation is tween ATP synthesis and oxidation.
the combination of oxidation by the ETS and phos- The functional linkage between oxidation and
phorylation by F1FO ATPase. Note that there is no phosphorylation depends on the integrity of the
physical linkage between oxidation and phosphor- inner mitochondrial membrane. All membranes

Chemistry, Biochemistry, and Cell Physiology

are somewhat permeable to protons, but the inner Myofibril

mitochondrial membrane is relatively resistant to
proton leak. If the protons pumped out of the mi- ATP ADP + Pi
tochondria by the ETS were to leak back into the
mitochondria, p would be dissipated, causing CPK
two effects on oxidative phosphorylation. First, Creatine Phosphocreatine
the ETS would continue at a high rate, pumping
protons and consuming oxygen in a futile effort to
Creatine Phosphocreatine
rebuild p. Second, the reduction in p would pre- Outer
CPK membrane
vent the mitochondria from producing ATP. Mito-
chondria that show high rates of respiration with
no ATP production are considered uncoupled. ATP ADP + Pi
While this state is disastrous for energy produc-
tion, it is an important mechanism to produce Inner
heat. Some mammals have specific proteins that membrane
facilitate the movement of protons across the in-
ner membrane. These uncoupling proteins are im- ATP
portant in mammals that experience cold stress,
such as newborns and hibernators. Mitochondrion

Figure 41 Phosphocreatine shuttle Phosphocreatine

Creatine phosphokinase enhances energy is produced by the mitochondrial enzyme creatine
stores and transfer phosphokinase (CPK) and diffuses to the myofibrils, where
another CPK enzyme regenerates the ATP.
Some of the energy stored first as ATP is used to
produce other high-energy phosphate compounds
of equivalent energy, such as phosphocreatine. A shuttle improves the efficiency of energy transfer
vertebrate muscle, for example, may have 5–10 two ways. First, creatine and phosphocreatine are
times more phosphocreatine than ATP, serving as smaller molecules than the adenylates and have
an energy store. When the muscle begins to work higher diffusion coefficients. Second, the absolute
at high intensity, ATP is consumed to support mus- concentrations of creatine and phosphocreatine
cle activity. The resulting decrease in [ATP] and in- are much greater than those of the adenylates, al-
crease in [ADP] drive the creatine phosphokinase lowing much steeper intracellular gradients to
(CPK) reaction in the direction of ATP production, form, which accelerates the rates of diffusion.
at the expense of phosphocreatine. As muscle ac-
tivity continues, the phosphocreatine pool is grad-
ually depleted, allowing muscles to preserve ATP
at normal levels for longer periods. Whereas the
Integration of Pathways of Energy
existing pool of ATP is sufficient for only a few sec-
onds of activity, the large phosphocreatine pool al- The metabolic traits exhibited by whole animals
lows muscle to maintain ATP levels and sustain can be traced back to the cellular pathways of en-
contractions for a much longer duration. ergy metabolism. Put simply, in order to remain in
In addition to bolstering energy stores, phos- energetic balance, cells must produce ATP at rates
phocreatine is a component of the phosphocrea- that match the ATP demand. Consider the situa-
tine shuttle, a pathway that improves the efficiency tion in a mammalian heart cell. We know from
of energy transfer within the cell (Figure 41). The rates of oxygen consumption that the heart con-
cycle begins with ATP produced by the mitochon- sumes ATP at a rate of about 30 µmol/min/g. Since
dria. CPK on the outer mitochondrial membrane the concentration of ATP doesn’t change during
uses this ATP to phosphorylate creatine. The normal activity, the heart cell must also produce
phosphocreatine diffuses from the mitochondria ATP at the same rate (30 µmol/min/g). Since the
to the myofibrils where another CPK uses the concentration of ATP is only about 5 µmol/g, at a
phosphocreatine to regenerate ATP. This CPK metabolic rate of 30 µmol/min/g, the heart turns
over the entire ATP pool several times per minute.

Chemistry, Biochemistry, and Cell Physiology

At this turnover rate, a cell that produces ATP at Oxygen and ATP control the balance
a rate only 10% less than the rate of demand between glycolysis and OXPHOS
would be depleted of ATP within two minutes. At
Glycolysis produces 2 mol of ATP for every mol of
the cellular level, the balance between energy-
glucose, but glucose oxidation yields 36 mol of ATP
consuming pathways and energy-producing path-
per mol of glucose. Despite the differences in en-
ways is orchestrated by the diverse regulators of
ergy yield, glycolysis and oxidative metabolism
metabolism, such as adenylates, redox balance,
both play important roles in energy metabolism.
Ca2, and carbon supply. These regulators “in-
Glycolysis, in addition to being able to operate
form” the cell of energy needs, and the metabolic
without oxygen, can produce ATP at much greater
pathways respond accordingly. What is interesting
rates than can oxidative metabolism. The condi-
about multicellular animals is that the needs of the
tions that allow such high rates also require the
cell are often superceded by the needs of the whole
pathway to be somewhat inefficient. In contrast,
organism. A liver cell, for example, not only re-
oxidative metabolism is very efficient in conserv-
sponds to its own metabolic needs but produces
ing chemical energy, but to do so, it is necessarily
energy substrates for the entire animal. When glu-
slow. Think of glycolysis as a high-performance
cose levels are low, the liver increases the rates of
sports car—useful to get somewhere fast but not
gluconeogenesis and glycogenolysis, releasing glu-
the best car for gas mileage. Oxidative metabo-
cose to the blood for use in other tissues. This al-
lism, by contrast, is the fuel-efficient compact car.
truistic response is imposed on the liver cell by
Like some suburban families, the cell maintains
hormones that affect the catalytic properties of the
both types of engines in working order, to be called
enzymes of intermediary metabolism, largely
upon for different needs.
through covalent modification, such as phosphor-
The sum of the cellular metabolic properties
Physical properties of fuels influence fuel
yields the whole animal metabolic patterns. Vari-
ations in animal metabolic rate are central to Each of the major metabolic fuels displays physical
many problems in animal physiology. About properties that influence how the fuel is stored and
allometric scaling of metabolic rate: large animals used. Carbohydrate is stored as large granules of
have lower mass-specific metabolic rates than glycogen, coated with water molecules that make
small animals. Animals control metabolic rate to up its hydration shell. Glycogen particles can be so
survive challenging conditions, such as environ- large that they interfere with cellular processes.
mental hypoxia, hypothermia, and dehydration. Some tissues, such as the mantle of bivalve mol-
In the accompanying feature, we describe the luscs, can safely accumulate high levels of glycogen,
ways physiologists measure whole animal meta- but if glycogen reached this high level in a muscle it
bolic rate in the lab and in the field (see Box 2, would prevent the muscle from contracting nor-
Methods and Model Systems: Metabolic Rate). mally. Although glycogen is readily mobilized, its
Metabolic strategies in animals address the physical properties prevent most cells from storing
constant fluctuations in nutrient availability, en- high levels. In contrast, lipid is stored at much
ergy demand, and environmental conditions. En- higher levels in the form of anhydrous, amorphous
suring the correct flow of energy requires droplets of triglyceride. These physical differences,
exquisite control of the pathways of intermediary coupled with the energy content of a given mass of
metabolism. Opposing pathways must be recipro- stored fuel, affect fuel selection. Cells can obtain
cally regulated to avoid a futile cycle: simultane- about 10 times more ATP from lipid than from the
ous synthesis and degradation of a metabolite. same mass of hydrated glycogen particles. Given
Similarly, the various alternatives must be utilized the advantage of lipid as an energy store, you might
in a way that takes into consideration the advan- wonder why animals use glycogen at all. Recall that
tages and disadvantages of each class of fuel. glycogen can be mobilized much faster than lipid,
These choices are also influenced by long-term and plays a vital role under conditions in which en-
and short-term metabolic priorities of the cells ergy is required very quickly, as in the “fight-or-
and organisms. flight” response. Most cells use a combination of
lipid and carbohydrate fuels to balance the advan-
tages and disadvantages of each fuel.

Chemistry, Biochemistry, and Cell Physiology


Metabolic Rate

If metabolism is literally the sum of all resting metabolic rate (RMR) must ensure that the an-
chemical reactions, then what exactly is meant by imal is unstressed and inactive at a neutral ambient
metabolic rate and how is it measured? Metabolic rate is temperature and has digested its most recent meal.
the overall flux through the pathways of energy produc- While this approach yields important information about
tion, which matches the rate of energy consumption. In the physiological hardwiring of an animal, it may not be
the presence of oxygen, the pathways that lead to produc- the best estimate of the animal’s metabolic rate under
tion of ATP consume carbon fuels and oxygen (O2), and normal conditions. Ecological physiologists are often
produce heat, carbon dioxide (CO2), and water. Many more interested in long-term metabolic rate of free-
physiological questions revolve around changes in meta- ranging animals in the natural setting. One of the most
bolic rate, and many approaches have been developed to common approaches to measuring field metabolic rate
measure the substrates and products of metabolism. is the doubly labeled water method. Most water in the
Direct calorimetry assesses metabolic rate in terms of body is composed of the most common isotopes of hy-
heat production, measured in energy units (joules). For drogen (1H) and oxygen (16O). To initiate a doubly labeled
purely pragmatic reasons (direct calorimetry requires water experiment, the animal of interest is captured and
expensive, specialized equipment), this is the least com- injected small volumes of water composed of less com-
mon way to measure metabolic rate. A more common ap- mon isotopes of hydrogen (e.g., 2H) and oxygen (18O).
proach to measuring metabolic rate is indirect Over time, the labeled hydrogen is lost from the body
calorimetry, in which the researcher measures the rate primarily as water, through evaporation, respiration,
of O2 consumption or CO2 production. To infer a metabolic and excretion. Likewise, labeled oxygen is also lost in
rate from these measurements, it is important to recog- water, but some is exchanged with the O in CO2. Thus,
nize where O2 is consumed (largely in the electron trans- the difference between the loss of labeled oxygen and
port system) and where CO2 is produced (primarily in the labeled hydrogen reflects the rate of CO2 production.
TCA cycle). The quantitative relationship between these This method works very well in air-breathing animals,
three estimates of metabolic rate—heat production, O2 but in water breathers, the rates of water flux are much
consumption, and CO2 production—depends on many too great to detect the impact of CO2 production on iso-
factors. You learned earlier in this chapter that the ratio tope ratios.
of CO2 produced/O2 consumed reflects the metabolic fuel.
Likewise, the oxycaloric relationships (O2 consumed/
q Hulbert, A. J., and P. L. Else. 2004. Basal metabolic rate: History,
joules released) depend on the nature of the fuel. composition, regulation, and usefulness. Physiological and Bio-
Each of these approaches for measuring metabolic chemical Zoology 77: 869–876.
rate requires that the researcher hold an animal under q Nagy, K. A. 2005. Field metabolic rate and body size. Journal of
controlled conditions and ensure that it remains in a Experimental Biology 208: 1621–1625.
constant, stable condition. A researcher interested in

The main way the cells regulate the balance phatase (PDHP). ATP, NADH, and acetyl CoA each
between fatty acids and carbohydrates is through activate PDHK, causing PDH to be converted to its
the mitochondrial enzyme pyruvate dehydroge- inactive, phosphorylated form. The activity of
nase (PDH). This enzyme is regulated allosterically PDHP, in contrast, is governed primarily by Ca2.
by ATP, acetyl CoA, and NADH. When cells have High [Ca2] stimulates PDHP, converting PDH to its
fatty acids available, their oxidation increases con- active dephosphorylated form.
centrations of ATP, NADH, and acetyl CoA. These
metabolites inhibit PDH, sparing pyruvate for glu-
coneogenesis. When energy stores are depleted, Fuel selection can be calculated from the
the concentrations of NADH, ATP, and acetyl CoA respiratory quotient
tend to decrease, which lessens the inhibition of Each pathway for oxidation of fuels demonstrates
PDH. These same metabolites also influence the characteristic relationships between the amount of
phosphorylation state of PDH by regulating the ac- (1) ATP produced, (2) oxygen consumed, and (3) CO2
tivities of PDH kinase (PDHK) and PDH phos- generated. The reason these parameters differ

Chemistry, Biochemistry, and Cell Physiology

among fuels can be traced back to the pathways of Energetic intermediates regulate the
degradation. Ratios of different combinations of balance between anabolism and
these three parameters provide important informa- catabolism
tion about fuel selection. The differences in the ra-
A cell activates pathways of energy production
tio of ATP produced to oxygen consumed (the ATP/O
when it needs energy, but when energy is abun-
ratio) can be traced to the reliance on FAD-linked
dant it stimulates anabolic pathways, storing nu-
enzymes. Each time an NADH molecule is produced
trients or producing building blocks for cell growth
in the mitochondria, oxidative phosphorylation can
or cell division. How do cells actually sense the
produce 3 molecules of ATP and consume 1 atom of
need for energy and regulate the transition be-
oxygen (ATP/O  3). When a molecule of FADH2 is
tween catabolism and anabolism? Many of the
produced, only 2 molecules of ATP can be generated
pathways we have discussed are sensitive to the
while consuming the same 1 atom of oxygen (ATP/
cellular indices of energetic status, primarily
O  2). Carbohydrate oxidation uses predominantly
acetyl CoA, adenylates, and NADH. Changes in the
NADH-linked enzymes, whereas lipid oxidation re-
concentration of these products reflect energy sta-
lies more heavily on FAD-linked enzymes. Because
tus and cause compensatory changes in metabolic
of this difference, carbohydrate yields more ATP for
pathways. When cells are “energy-rich,” the con-
a given volume of oxygen. This difference has an ef-
centrations of acetyl CoA, NADH, and ATP are rel-
fect on the fuel preference of at least some animals
atively high and the concentrations of CoA, NAD,
that live at low oxygen levels. For example, the
ADP, and AMP are low. Consider how these
heart of most humans uses lipid as a major fuel. In
metabolites stimulate gluconeogenesis while in-
contrast, humans that have adapted to high alti-
hibiting glycolysis (Figure 42). By matching the
tude, such as the natives of the high Andes, rely
more heavily on glucose oxidation. Of course, in Glucose
more extreme hypoxia and anoxia, animals have lit-
tle choice but to rely on glycolysis.
Differences in the ratio of CO2 produced to O2
Fructose 6-phosphate
consumed, known as the respiratory quotient
(RQ), arise from the pathways of oxidation. Glu- –AMP
cose has six carbons, and oxidizing it completely +AMP PFK FBPase
to 6 CO2 yields 2 NADH in the cytoplasm, 2 NADH – ATP
via PDH, 6 NADH via the TCA cycle, and 2 FADH2
Fructose 1,6-biphosphate
via succinate dehydrogenase. The 12 reducing
Glycolysis Gluconeogenesis
equivalents consume 12 atoms of oxygen, or 6
molecules of O2. Thus, carbohydrate oxidation
yields an RQ of 1 (6 mol of CO2 to 6 mol of O2). In
contrast, oxidation of fatty acids generates an RQ
of about 0.7, although the exact number depends Phosphoenol pyruvate
on the specific fatty acid. Consider the pathway of
palmitate oxidation. As a 16-carbon fatty acid, it
generates 16 mol of CO2 per mol of palmitate. –Acetyl CoA PK Oxaloacetate
Seven cycles of -oxidation are required to break PC +Acetyl CoA
palmitate into 8 molecules of acetyl CoA, yielding Pyruvate
7 FADH2 and 7 NADH. Oxidation of the 8 acetyl
CoA in the TCA cycle yields 24 NADH and 8 PDHa PDHb –ATP
FADH2. Oxidation of the 46 reducing equivalents –Acetyl CoA
consumes 23 mol of O2, giving an RQ of 0.7 (16 mol
of CO2 to 23 mol of O2). Because of these charac- +Acetyl CoA
teristic relationships between RQ and fuel oxida- +ATP Acetyl CoA
tion, measurement of CO2 production and O2 Figure 42 Reciprocal regulation of glucose
consumption of whole animals can provide impor- metabolism High-energy compounds, such as ATP,
tant insight into the pathways that are being used acetyl CoA, and NADH, inhibit glycolysis and stimulate
to support energy metabolism. gluconeogenesis at key regulatory enzymes.

Chemistry, Biochemistry, and Cell Physiology

rates of ATP synthesis with rates of ATP utiliza- themselves from the environment, giving them con-
tion, cells are able to defend ATP concentrations trol over intracellular conditions. Second, mem-
within a narrow range. branes help cells organize intracellular pathways
Animals also use other metabolites to recipro- into discrete subcellular compartments, including
cally regulate opposing pathways. When meta- organelles. Separation of processes also requires
bolic conditions induce cells to commit to fatty acid specific mechanisms to transfer molecules across
synthesis, the increases in the levels of malonyl the membranes. Many complex physiological prop-
CoA block fatty acid oxidation by inhibiting CPT-1. erties and responses depend on cellular transport
Cells further separate anabolism and catabolism and transfers between subcellular compartments.
using tissue specializations. The liver has the en- Ultimately, the cellular properties that determine
zymes for ketogenesis but cannot break down ke- physiological function are controlled through regu-
tone bodies. Muscles have the enzymes for ketolysis lation of gene expression.
but cannot synthesize ketone bodies. In fact, the
control of energy metabolism in complex animals
reflects a division of labor such that some tissues
Membrane Structure
become servile to others. Liver and adipose tissue
perform important functions for whole animal Cellular membranes are composed of phospho-
metabolic balance, giving lower priority to their lipids, other lipids, and diverse proteins. The
own cellular and metabolic needs. fluid mosaic model, shown in Figure 43, illus-
trates the structural features of biological mem-
branes. Each of the two layers is a sheet of lipid
molecules arranged side by side. The surfaces of
2 CO N CEP T C HE C K the lipid bilayer are composed of the polar head
8. Compare the four types of macromolecules. groups of phospholipids, and the internal hy-
Discuss how variation in structure arises in drophobic core is composed of long fatty acid
each class. chains of the phospholipids attached through van
9. Distinguish between the following types of der Waals forces.
reactions: anabolic, catabolic, amphibolic,
10. How is oxidation coupled to phosphorylation in The lipid profile affects membrane
mitochondrial oxidative phosphorylation? properties
11. Compare the pathways of glucose metabolism Animals produce specialized membranes with
(synthesis and degradation) under (a) high unique molecular signatures by varying the struc-
versus low energy conditions and (b) normal
versus low oxygen conditions.
tures and proportions of the different types of lipid.
Much of the variation can be attributed to the profile
12. Under what conditions is it more advantageous
to use carbohydrate rather than lipid as a of phosphoglycerides, the most abundant of which
metabolic fuel? are phosphatidylcholine (PC), phosphatidylserine
(PS), and phosphatidylethanolamine (PE). Recall
from earlier in this chapter that each of these phos-
pholipids is really a class of molecules with con-
Cell Physiology stituent fatty acids that differ in chain length and
In the opening essay, we discussed how the evo- saturation. Although phosphoglycerides are the
lutionary origins of animals required a new rela- most abundant molecules in the bilayer, membranes
tionship between cells to foster multicellular also possess other lipids, including sphingolipids,
relationships. Cellular membranes1 perform two glycolipids, and cholesterol, as well as many pro-
main roles that are central to multicellularity and teins. Glycolipids resemble phospholipids, but with
cellular function. First, they allow cells to isolate complex carbohydrate modifications that impart a
negative charge to the polar head group. Nerve cells
possess high concentrations of sphingolipids and
Cellular membranes refer to all of the membranes within
glycolipids because they alter the electrical proper-
a cell, including the plasma membrane (or cell membrane)
that surrounds the cell and the membranes that form the ties of the membrane. Glycolipids are also important
organelles. in communication between cells.

Chemistry, Biochemistry, and Cell Physiology

The unusual ability of cholesterol

Sugar residues to increase fluidity while decreas-
of glycoprotein
ing permeability provides animals
Glycoprotein with an important mechanism for
controlling membrane properties.
Lipid membranes are
protein While the fluid mosaic model illus-
trates the general relationships be-
tween lipid and protein variation in
Peripheral membrane proteins, it underem-
proteins Integral Cholesterol
phasizes the spatial variation seen
in membrane lipids (Figure 45).
Figure 43 Fluid mosaic model Membranes are composed of lipids The inner and outer layers of the
such as phospholipids, cholesterol, and glycolipids. Proteins can be embedded in phospholipid bilayer typically pos-
the lipid bilayer. Each of the elements moves laterally within the membrane,
sess different types of lipids. PE
giving it a functional fluidity.
and PS are found almost exclu-
sively in the inner leaflet, whereas
Cholesterol has an unusual role in mem- PC is concentrated in the outer leaflet. Glycolipids
branes. Although it is absent from some mem- are found only in the outer leaflet of the mem-
branes, such as mitochondrial membranes, brane. Membranes also possess discrete regions
cholesterol can compose almost half the lipid com- that are enriched in cholesterol and glycolipids.
ponent of other membranes. Cholesterol influ- These lipid rafts serve two important functions.
ences membrane properties in complex ways Their molecular composition causes a slight thick-
because of the way it integrates into the lipid bi- ening of the lipid bilayer, which recruits phospho-
layer (Figure 44). One end of the molecule inter- lipids with longer chain fatty acids and proteins
acts with phospholipids near the polar head with relatively long transmembrane domains. Be-
groups, filling gaps between phospholipids to re- cause of the distinct molecular composition of lipid
duce the permeability to low-molecular-weight rafts, they can act as microcompartments within
solutes. Cholesterol also disrupts the interactions the cell, providing an additional way to spatially
between fatty acids, enhancing membrane fluidity. organize pathways.

CH CH2 Environmental stress can alter membrane
CH3 fluidity

CH3 CH3 An essential component of the fluid mosaic model

is the ability of the constituents to move through-
out the membrane. Phospholipids and proteins
Cholesterol can rotate in position as well as move laterally
through the membrane. Membrane fluidity de-
pends on the properties of the membrane lipids,
which are influenced by the physical environment.
Cells regulate the fluidity of the membrane by con-
trolling the nature of lipids to achieve the appro-
priate degree of molecular movement. Low
temperature, for example, can strengthen the van
Figure 44 Unusual membrane properties of der Waals forces between membrane lipids, re-
cholesterol Cholesterol strengthens the interactions stricting molecular movement within the mem-
between phospholipid polar head groups while disrupting the brane (Figure 46). Since this can adversely affect
interactions between fatty acid tails. membrane function, many animals actively

Chemistry, Biochemistry, and Cell Physiology

Extracellular fluid
Membrane proteins have
important structural and regu-
Cholesterol latory roles within cells. They
contribute to structural support
by linking the intracellular cy-
toskeleton to the extracellular
matrix. Many of the intrinsic
membrane proteins are recep-
tors that are part of complex
signaling pathways. Because
membranes are physical barri-
Cytoplasm Lipid raft
ers to the free movement of
Figure 45 Membrane heterogeneity Cellular membranes are many vital organic and inor-
heterogeneous in composition. Most cells maintain distinct profiles in inner and outer ganic solutes, cells use integral
monolayers, sometimes exchanging phospholipids between layers. Lipid rafts are proteins to transport molecules
regions of the plasma membrane that accumulate cholesterol and glycolipids, across membranes.
thickening the membrane. These thicker regions preferentially recruit proteins with
longer transmembrane domains.

remodel their membranes to compensate for the Transport Across Cellular

effects of the physical environment. By altering the Membranes
membrane lipid profile, they can keep membrane
fluidity constant. This pattern of membrane regu- Many cellular processes depend on the ability to
lation, is called homeoviscous adaptation. move molecules across membranes. A cell must be
able to bring nutrients across its plasma mem-
brane and expel end products. Hormones synthe-
Membranes possess integral and sized within the cell must be processed and
peripheral proteins packaged for secretion. All animal cells must be
Protein is an important constituent of most cellu- able to move specific ions across the plasma mem-
lar membranes, in some cases making up more brane to control their ionic and osmotic proper-
than half the mass of the membrane. Integral ties. Specific integral membrane proteins mediate
membrane proteins are tightly bound to the mem- these transport processes. The kinetic properties
brane, either embedded in the bilayer or spanning of a transporter are similar to those of enzymes,
the entire membrane. Peripheral membrane with an affinity constant (Km) and a maximal veloc-
proteins have a weaker association with the lipid ity (Jmax). The three main classes of membrane
bilayer, typically binding to integral membrane pro- transport are passive diffusion, facilitated diffu-
teins or glycolipids. The different relationships be- sion, and active transport. These classes of trans-
tween the bilayer and membrane proteins are port are distinguished by the direction of
shown in Figure 47. transport, the nature of the carriers, and the role
of energy in the process (Figure 48).

Lipid-soluble molecules cross membranes

by passive diffusion
Cold Although membranes are barriers to the move-
ment of many molecules, some molecules cross
Warm membranes without a transporter. The ability of a
molecule to freely cross a biological membrane de-
pends on its hydrophobicity. Many molecules,
Liquid crystalline Gel such as steroid hormones, are freely soluble in
Figure 46 Temperature and membrane fluidity lipid. When these molecules encounter a cell
Temperature alters the fluidity of membranes by changing membrane, they dissolve into the lipid bilayer and
the interactions between phospholipids. escape to the other side. Both influx and efflux oc-

Chemistry, Biochemistry, and Cell Physiology

cur simultaneously, but the net

movement (influx minus efflux) de- Peripheral
pends on the concentration gradi- protein
ent. The net movement of molecules P
P Glycolipid
is from high concentration to low anchor
concentration. The steeper the con-
centration gradient, the greater the
rate of movement across the mem-
brane. This type of transport is β-barrel

called passive diffusion. No spe- Single Multiple

pass pass Peripheral
cific transporters are required, and protein
α-helix α-helix
no energy, beyond the concentration
gradient itself, is required. Figure 47 Integral membrane proteins Membrane proteins can
demonstrate many different types of relationships with membranes. Each membrane
protein has within its structure hydrophobic regions that interact favorably with the
Membrane proteins can bilayer. Depending on the protein, these regions can be
-helices or -barrels.
facilitate the diffusion of Transmembrane proteins span the entire bilayer, exposing regions to both sides of the
impermeant molecules membrane. Often these exposed regions possess modifications, such as the
Hydrophilic molecules cross mem- carbohydrate chains of glycoproteins. Peripheral membrane proteins are not
branes by other pathways that involve embedded within the membrane but associate with exposed regions of integral
membrane proteins.
specific transport proteins. If the con-
centration gradient is favourable, the Outside of cell
molecule may cross the membrane
by facilitated diffusion. As with Lipid-soluble
passive diffusion, no energy beyond
that of the concentration gradient is Concentration
required to drive transport, but with
facilitated diffusion a protein is re-
quired to carry the molecule across
the membrane. Three main types of
proteins carry out facilitated diffu-
sion: ion channels, porins, and per-
meases (see Figure 49). Passive Channel Permease Active
diffusion transport
Ion channels are membrane
Facilitated diffusion
proteins that form pores through Inside of cell
which only specific ions may pass,
and only when the channel is open. Figure 48 Modes of membrane transport The mechanisms of transport
The channels are specific to one or across cellular membranes depend on the lipid solubility of the solute as well as the
sometimes two ions. Ca2 channels, direction and magnitude of the concentration gradient. Passive diffusion needs no
for instance, possess a structure that carrier, as lipid-soluble solutes move freely across the membrane. Facilitated
diffusion carries impermeant solutes across the membrane on protein carriers,
allows the free movement of Ca2,
including channels (either ion channels or porins) and permeases. Solutes can also be
but does not allow other cations
2   transported by active transport, which can move molecules against a concentration
such as Mg , K , or Na to cross at gradient.
appreciable rates. The specificity of
transport is due to a structural component of the IP3, is present. Voltage-gated channels are
channel known as the selectivity filter. The chan- opened or closed in response to membrane poten-
nel can be opened in response to cellular condi- tial. For example, K channels in muscle and neu-
tions. Ligand-gated channels are opened when rons open when the membrane depolarizes.
specific regulatory molecules are present. One im- Mechanogated channels are regulated through
portant ligand-gated channel is the Ca2 channel interactions with the subcellular proteins that
sensitive to inositol triphosphate (IP3); this channel make up the cytoskeleton. Changes in cell shape,
induces the release of Ca2 stores when its ligand, such as cell swelling, alter the arrangement of the

Chemistry, Biochemistry, and Cell Physiology

Δψ Δψ

(a) Voltage-gated (b) Ligand-gated (c) Mechanogated

Figure 49 Carriers involved in facilitated diffusion Channels are proteins that

mediate facilitated diffusion of ions and other metabolites. Channels typically exist in either a
closed or an open conformation. They are opened by specific triggers, including specific ligands,
voltage conditions, or physical associations with structural elements.

cytoskeleton. Upon sensing the changes in the tration. In contrast, cells use active transport to
cytoskeleton, mechanogated channels may open move molecules across membranes against con-
or close. centration gradients. Two main forms of active
Porins are large channels that function in transport are distinguished by the source of the en-
similar ways to ion channels but permit the pas- ergy that drives the process. In primary active
sage of much larger molecules. Mitochondria have transport, the carrier protein uses an exergonic re-
a porin in the outer membrane that facilitates the action to provide the energy to transport a molecule.
transfer of low-molecular-weight molecules from The other form of active transport, called secondary
the cytoplasm to the mitochondria. Aquaporins active transport, couples the movement of one
are water channels in the plasma membranes; molecule to the movement of a second molecule.
each aquaporin molecule can transport 3 billion The most common primary active transporters
water molecules per second. Some aquaporins, use the hydrolysis of ATP to provide the necessary
called aquaglyceroporins, are also capable of energy. Three general classes of ATP-dependent
transporting nonwater molecules, such as glycerol transporters, or ATPases, mediate primary active
and possibly urea. Aquaporins may also be in- transport: P-type ATPases, F-type (or V-type) AT-
volved in transport of gases across membranes. Pases, and ABC transporters. P-type ATPases use
The third type of protein that facilitates diffu- ATP hydrolysis to pump specific ions across mem-
sion is a permease. Rather than creating a pore for branes. For example, animal cells have a Na/K
a molecule, a permease functions more like an en- ATPase in the cell membrane that extrudes Na
zyme. It binds the substrate and then undergoes a from the cell in exchange for K. Many tissues have
conformation change that causes the carrier to re- Ca2 ATPases to transport Ca2 across membranes.
lease the substrate to the other side. Several tissues F-type and V-type ATPases are structurally re-
possess glucose permease, a transporter that allows lated ATPases that pump H across membranes
glucose to enter cells, passing from high concentra- using the energy of ATP hydrolysis. The mitochon-
tion to low concentration. Unlike porins and ion drial F-type ATPase operates in reverse, using H
channels, permeases can become saturated with movements down electrochemical gradients to
substrate at high concentration, such that the trans- provide the energy for ATP synthesis. The V-type
port process depends on how quickly the permease ATPases allow cells and organelles to extrude pro-
can carry its substrate across the membrane. tons to acidify a compartment, such as the lumen
of the lysosome or the inside of the stomach.
The ABC transporters carry large organic mol-
Active transporters use energy to pump ecules across the cell membrane. Cells often use
molecules against gradients ABC transporters to export toxins from the cell.
In passive and facilitated diffusion, molecules can The multidrug resistance protein, an important
move only from high concentration to low concen- ABC transporter, is often linked to types of cancers

Chemistry, Biochemistry, and Cell Physiology

that become resistant to chemotherapy. Some can- ganisms. Electrical signaling is not, however, a
cerous cells survive chemotherapy by transporting unique property of nerve and muscle cells. Several
the toxic drug out of the cell before the chemother- other types of cells use electrical signals, including
apeutic agent can kill it. fertilized eggs and hormone-secreting cells.
Secondary active transport uses the energy
held in the electrochemical gradient of one mole-
The interior of the membrane is
cule to provide the energy to drive another mole-
electronegative at rest
cule against its gradient. If the molecules move in
opposite directions, the carrier is called an Membrane potential can be measured using a mi-
antiport, or exchanger. For example, red blood croelectrode. Microelectrodes consist of a thin
cells use a Cl/HCO3 exchanger (also called band 3) recording electrode encased in a very fine-tipped
to drive the transport of these ions across the mem- glass pipette that can be inserted through the cell
brane. The direction of ion movement by this car- membrane into the cell. The microelectrode is
rier depends on the relative gradients of the two connected via a voltmeter to a reference electrode
ions. Alternatively, a symport, or cotransporter, that is immersed in the solution outside the cell.
is used to move molecules in the same direction. The voltmeter measures the voltage drop across
For example, intestinal cells use a Na-glucose co- the circuit caused by the membrane potential (Vm).
transporter to import glucose against its concentra- In most animal cells, the membrane potential is
tion gradient, driven by a greater inward Na between 5 and 100 mV. By convention, the
electrochemical gradient. membrane potential is expressed relative to the
All of these transport processes influence chem- voltage outside the cell. Thus, the negative value
ical gradients across membranes, but only a subset for Vm means that the interior of the cell mem-
of transporters affect the electrical gradient. Carri- brane is more electronegative than the exterior of
ers that transport uncharged molecules, such as the the cell membrane.
glucose permease, are termed electroneutral car-
riers. Similarly, carriers such as the Cl/HCO3 ex-
changer that exchange two ions of the same charge Ionic concentration gradients and
are also electroneutral. In contrast, the carriers that permeability establish membrane
transfer a charge across the membrane are called potential
electrogenic carriers. When we discuss Na/K Only two factors are required to establish a poten-
ATPase throughout this text, keep in mind that it is tial difference across a membrane: a concentration
an electrogenic carrier because it exchanges 3 Na gradient for an ion and a membrane that is perme-
for 2 K ions. able to that ion. Consider a situation where two so-
lutions are separated by a membrane that is
impermeable to ions (Figure 50). Assume that the
interior of the cell contains 100 mM KCl and 10 mM
Membrane Potential NaCl, and the extracellular fluid contains 100 mM
All animal cells maintain a voltage difference NaCl and 10 mM KCl. The concentration gradient
across their cell membranes, as well as some or- for K (100 mM inside the cell and 10 mM outside
ganelle membranes, such as the mitochondrial the cell) favors outward movement, whereas the
membrane. This voltage difference represents a concentration gradient for Na (100 mM outside
source of potential energy that cells can harness to and 10 mM inside the cell) favors inward move-
move molecules across membranes. The voltage ment. There is no gradient for the movement of Cl
difference is termed the resting membrane poten- (because the concentration of Cl is 110 mM both
tial difference, or the membrane potential, for inside and outside the cell). The solutions on either
short. In addition to using the membrane potential side of the membrane are also electroneutral, with
as a source of energy, excitable cells use changes equal numbers of anions and cations.
in membrane potential as communication To create a membrane potential, we insert
signals. This property is particularly important channels that allow the passage of K, but no other
for nerve and muscle cells, and thus the ion. The concentration gradient will cause K to
membrane potential is critical for allowing move out of the cell along the concentration gradi-
the coordinated movements of cells and or- ent, creating a local region of electronegativity on

Chemistry, Biochemistry, and Cell Physiology

K+ ion
Cl– ion Na+ ion

Inside cell: 100 mM KCl, 10 mM NaCl

Outside cell: 10 mM KCl, 100 mM NaCl

Inside cell Outside cell gradient

– + –
– + + – – – + –
+ – – – + +
– + –
– – + + + – +
+ + + – + –
+ – + – + +
– + – – – + + –
– – + – – + + –
+ + – – + – –
– – +
– – – + + + – + –
+ – + + +
+ + + – + – +– ++ + +
– – – – –
+ – +
– – – + + – ++ –
– –
+ + – – + – + + –
– + + + + +
+ + +
+ + – – – + – – + +
– – –

1 No permeability to any ion 2 K+ channels open, 3 Outward concentration

K+ exits cell gradient eventually equals
inward electrical gradient

Figure 50 Potassium movements and membrane potential

the inner face of the membrane (where K left) where R is the gas constant, T is the temperature
and a local region of electropositivity on the outer (Kelvin), z is the valence of the ion, F is the Fara-
face of the membrane (where K appeared). This day constant (23,062 cal/V-mol), and [X] is the mo-
excess negative charge at the inside face of the lar concentration of the ion. In our example,
membrane generates an electrical force that tends [K]outside  10 mM and [K]inside  100 mM, result-
to draw positive charges back into the cell. As ing in EK  60 mV. In other words, the force driv-
more K leaves the cell, the electrical force gradu- ing the outward movement of K resulting from its
ally increases to a level that exactly balances the 10-fold concentration gradient can be exactly bal-
driving force from the K concentration gradient. anced by a 60 mV excess of negative charge inside
Potassium ions continue to move across the mem- the membrane (a membrane potential of 60 mV).
brane, but their inward and outward fluxes ex- The equilibrium potential for a particular ion
actly balance each other. The potential difference is often termed its reversal potential, because
across the membrane under these equilibrium the direction of ion movement across the mem-
conditions is termed the equilibrium potential brane changes when the voltage difference across
for that ion (Eion). Because only a single ion can the membrane exceeds this level. In the case of
move across the membrane in this hypothetical our hypothetical example, net K flux was down
example, the equilibrium potential is equivalent to its concentration gradient from the inside to the
the resting membrane potential (Eion  Vm). outside of the cell until the membrane potential
For a given concentration gradient, it is possi- difference reached 60 mV. If the membrane po-
ble to calculate the equilibrium potential for an ion tential were to become even more negative, the
using the Nernst equation, net movement of K would be from the outside of
the cell back to the inside—against its concentra-
RT 3X4 outside tion gradient. Note that the actual number of ions
3X4 inside
zF that need to move across the membrane before

Chemistry, Biochemistry, and Cell Physiology

reaching the equilibrium potential is actually very and permeabilities of all of the relevant ions (see
small (less than 1/100,000 of the total K ions Box 3, Mathematical Underpinnings: The Gold-
within a typical cell), and does not result in a man Equation). The Goldman equation essentially
measurable change in the overall K concentra- represents the sum of the equilibrium potentials
tion either inside or outside the cell. for all of the relevant ions, with a weighting factor
It is important to emphasize that the membrane that takes into account the relative permeabilities
potential is the result of extremely small differences of the ions. The influence of each ion over the
in the number of charged molecules immediately overall membrane potential is thus proportional to
adjacent to the membrane—a difference that is too its permeability. For example, resting neurons are
small to detectably affect the overall ion concentra- more permeable to K than to the other ions, and
tion of the cytoplasm or extracellular fluid. The lo- as a result, K plays the major role in setting the
calization of the charge difference immediately resting membrane potential of neurons.
adjacent to the membrane arises because the cell
membrane acts as a capacitor. A capacitor is a de-
The Na/K ATPase establishes
vice containing two electrically conductive materi-
concentration gradients
als separated by an insulator, a very thin layer of
a nonconducting material. Electrical charges can Active pumping of Na and K ions by the electro-
interact with each other across the insulator if the genic Na/KATPase is responsible for establish-
layer is sufficiently thin. In a cell, the cytoplasm ing the concentration gradients for these ions
and the extracellular fluid are conducting materi- across the cell membrane. Ultimately it is these
als, whereas the lipid bilayer of the cell membrane concentration gradients (along with the selective
is the insulator. The excess positive charge along permeability of the membrane) that establish the
the outside of the membrane attracts the excess membrane potential. The Na/KATPase is also
negative charge along the intracellular face of the responsible for maintaining the resting membrane
membrane. These electrical interactions can only potential. Although most membranes are only
occur across very small distances, and do not af- sparingly permeable to Na at rest, a small
fect ions in the bulk phase of the cytoplasm or ex- amount of Na does leak into the cell down its
tracellular fluid. Thus, the membrane potential electrochemical gradient, while K leaks out.
occurs only in the area immediately adjacent to Without appropriate compensation, these ion
the membrane. movements would result in the dissipation of the
Na and K concentration gradients that are
needed to establish the membrane potential. Cells
Potassium plays the major role in use the Na/K ATPase to compensate for the leak-
establishing membrane potential age of Na and K ions. If you poison the Na/K
In our hypothetical example neither Na nor Cl ATPase with a drug called ouabain, the membrane
affected the membrane potential because there potential difference of the cell slowly decays over
was no concentration gradient for Cl and because the course of a few hours, eventually reaching a
the membrane was not permeable to either of value of 0 mV.
these ions. Of course, the situation in real cells is
not so simple, since there are several ions that dif-
fer in concentration between the inside and the Changes in membrane permeability alter
outside of the cell, and real membranes have vary- membrane potential
ing degrees of permeability to multiple ions. For Because ion permeability is a major factor in-
most cells, the primary ions that affect the mem- volved in establishing the resting membrane po-
brane potential are K, Na, and Cl because they tential, changes in ion permeability cause changes
can move across membranes and there are differ- in membrane potential. Excitable cells such as
ences in their intracellular and extracellular con- neurons and muscle cells alter the permeability of
centrations. A modification of the Nernst equation, their membranes to generate changes in mem-
the Goldman-Hodgkin-Katz Constant Field equa- brane potentials. We can use the Nernst equation
tion (usually referred to as the Goldman to predict the nature of the ion movements follow-
equation) can be used to calculate the resting ing changes in membrane permeabilities. For ex-
membrane potential based on the concentrations ample, in mammalian neurons the concentration

Chemistry, Biochemistry, and Cell Physiology


The Goldman Equation

The Goldman-Hodgkin-Katz Constant The two terms for K permeability also cancel out,
Field equation (often simply referred to as the leaving an equation that is equivalent to the Nernst
Goldman equation or GHK), allows the estimation of the equation for potassium (with the exception of the va-
membrane potential based on the concentrations, va- lence term, z, which is neglected because potassium
lences, and relative permeabilities of a series of ions. has a valance of 1). Notice, however, that if we do the
Since most plasma membranes under resting condi- same exercise assuming that the membrane is perme-
tions have appreciable permeability only to postassium, able only to chloride, we end up with an equation that is
sodium, and chloride, the Goldman equation can be similar to the Nernst equation, except that it neglects
written as follows: the valence and has the intracellular concentration in

RT PK 3K 4 o  PNa 3 Na 4 o  PCl 3 Cl 4 i
   the numerator and the extracellular concentration in
Em  the denominator, rather than the other way around. Re-
PK 3 K 4 i  PNa 3 Na 4 i  PCl 3 Cl 4 o
F call that one of the rules of logarithms is that ln x  ln
where Pion is the permeability of the membrane to that (1/x). By inverting the ratio of the concentrations of chlo-
ion and [ion]o and [ion]i represent the extracellular and ride, the Goldman equation takes into account the fact
intracellular concentrations, repectively, of a given ion. that chloride has a valence of 1.
From the Goldman equation, the impact of ion per- In addition to providing an estimate of the resting
meability on the membrane potential is clear. Any ion membrane potential, the Goldman equation allows the
with a low permeability has little effect on the mem- estimation of the membrane potential during electrical
brane potential, even if there is a large concentration signaling. For example, when a large number of Na
gradient across the membrane for that ion. Notice that channels open within the membrane (as is the case dur-
if the permeability of the membrane for an ion is zero, ing signaling in nerve cells), the permeability of the
then the term for that ion drops out of the equation. For membrane to Na increases greatly. In the case of neu-
example, consider the case of a membrane that is im- ral signaling, this increase in Na permeability is so
permeable to Na and Cl. In this case, the Goldman large that PNa becomes much greater than PK and PCl.
equation simplifies to Under these conditions, the Goldman equation is domi-
nated by the term for Na, and the membrane potential
RT PK 3 K 4 o

approaches the equilibrium potential for Na as calcu-
PK 3 K 4 i
F lated by the Nernst equation.

of Na is typically about 10-fold greater outside movement until the membrane potential reaches
the cell, so ENa  58 mV. In contrast, K concen- the equilibrium potential for K of 90 mV. The
tration outside the cell is only about 1/40 of that loss of positive charges from the interior of the cell
inside the cell, so EK  90 mV. The resting mem- results in a hyperpolarization. Many cells use cy-
brane potential of neurons is typically about 70 cles of depolarization, hyperpolarization, and re-
mV. If the Na permeability of the membrane in- polarization as communication signals.
creases (as a result of the opening of Na chan-
nels), Na will enter the cell, because both the
electrical and concentration gradients favor in-
Subcellular Organization
ward Na movement until the membrane poten- Eukaryotes rely on complex intracellular organi-
tial reaches the equilibrium potential for Na of zation to orchestrate the many processes required
58 mV. The resulting inward Na movement for life. Central to the diversity in physiological
causes a reduction in the membrane potential function is the ability of individual cells to perform
termed a depolarization (Figure 51). In contrast, specific roles for the tissue and animal. We gain a
if the K permeability of the membrane increases clearer understanding of complex physiological
(as a result of the opening of K channels) K will systems by studying the role of the various cellular
move out of the cell, because both its concentra- compartments that contribute to the process.
tion and electrical gradients favor outward K

Chemistry, Biochemistry, and Cell Physiology

Experimentally, it is easier to measure the relative cannot be more negative than 75 mV or more positive
permeability of ions, rather than the absolute perme- than 55 mV because there are no chemical gradients
ability. Hence, the Goldman equation is often rewritten large enough to produce larger membrane potential dif-
after dividing each term by PK. ferences. At rest, the membrane does not quite reach
the equilibrium potential for K because of the compet-
RT 3K 4 o  PNa>PK 3 Na 4 o  PCl>PK 3Cl 4 i ing effects of Na, but because Na permeability is rel-
3 K 4 i  PNa>PK 3 Na 4 i  PCl>PK 3Cl 4 o
F atively low its influence is small, and the membrane
potential is close to the K equilibrium potential. Note
For a cell such as a squid giant axon, the following val- that the squid giant axon also has appreciable perme-
ues can be used to calculate the membrane potential: ability to Cl (about half that of K). In fact, some cell
[K]i  400 mM and [K]o  20 mM membranes (e.g., in muscle cells) are more permeable
to Cl than they are to K. However, even in this case, K
[Na]i  50 mM and [Na]o  440 mM
plays the major role in establishing the membrane po-
[Cl]i  51 mM and [Cl]o  560 mM tential. The Na/K ATPase actively pumps Na and K
PNa / PK  0.04 ions to establish their concentration gradients. The K
PCl / PK  0.45 concentration gradient sets the resting membrane po-
tential difference, and Cl ions passively distribute
Substituting these values into the Goldman equation themselves across the membrane in response. Thus, in
predicts the membrane potential of this squid giant the case of Cl ions, the intracellular and extracellular
axon to be 60 mV at rest, which is a good approxima- Cl levels are a consequence rather than a cause of the
tion of the measured resting membrane potential. resting membrane potential.
Returning to the Nernst equation, we can also calcu-
late the equilibrium potentials for each of these ions.
Using the concentrations relevant to the squid giant
axon, the equilibrium potential is 75 mV for K, 55 Reference
mV for Na, and 60 mV for Cl. These equilibrium po- q Hodgkin, A. L., and A. F. Huxley. 1952. A quantitative description
tentials establish the “boundary conditions” for the of membrane current and its application to conduction and exci-
membrane potential. That is, the membrane potential tation in the nerve. Journal of Physiology 117: 500–544.

Mitochondria are the powerhouse of the cell of any biological membrane in animals. Mitochon-
Mitochondria are complex organelles, possessing dria organize the inner membrane into layers, or
intricate networks of membranes (Figure 52). The lamellae, that are tightly folded. In some tissues, as
innermost compartment is the mitochondrial ma- much as 70 m2 of mitochondrial inner membrane
trix, delimited by the inner mitochondrial mem- can be folded into a 1-cm3 volume of mitochondria.
brane. The outer mitochondrial membrane Mitochondrial structure varies greatly among
surrounds the organelle and creates another com- cell types. Many cells, such as liver, contain hun-
partment called the intermembrane space. Each of dreds of individual oblong mitochondria scattered
these compartments has its own complement of throughout the cell. These individual mitochon-
enzymes and performs different functions for the dria are rapidly transported throughout the cell.
mitochondria and the cell. The matrix houses the Some cells organize their mitochondria into net-
enzymes and metabolites of the TCA cycle. The in- works of interconnected organelles called the
ner mitochondrial membrane, which is often mitochondrial reticulum, which is constantly re-
highly convoluted, holds the enzymes of oxidative modeled by enzymes that mediate its fission and
phosphorylation and all the transporters neces- fusion.
sary to move metabolites in and out of the mito- Earlier in this chapter you learned that mito-
chondria. About 80% of the mass of the inner chondria possess the enzymes of oxidative phos-
membrane is protein, the highest protein content phorylation, and make most of the ATP a cell

Chemistry, Biochemistry, and Cell Physiology

Na+ channel Na+ K+ channel


Open Open
Na+ K+

channels channels

+50 +50 +50

0 0 0


–50 –50 –50

–100 –100 –100

Time (msec) Time (msec) Time (msec)

Figure 51 Hyperpolarization and depolarization The gradients of Na and K

across the cell membrane largely determine the resting membrane potential. When specific ion
channels open, the movement of ions changes the membrane potential. If K moves out of the
cell, the magnitude of the membrane potential increases (hyperpolarization). If Na moves into
the cell, the magnitude of the membrane potential decreases (depolarization).

requires. Cells frequently respond to changes in It has an important role in maintaining cell struc-
energy demand by altering their levels of mito- ture, acting as a frame upon which the cell mem-
chondria, using both biosynthetic and degradative brane is mounted. It gives the cell its characteristic
pathways. Most of the genes required for synthe- external shape and also supports and organizes in-
sis of mitochondrial proteins are located in the nu- tracellular membranes. Organelle networks such as
cleus. Mitochondrial biogenesis requires that each the endoplasmic reticulum and Golgi apparatus are
of these genes be expressed in unison to produce mounted on the cytoskeleton. The cytoskeleton is
the hundreds of proteins needed for new mito- dynamic in structure, under constant reorganiza-
chondria or an extension of the mitochondrial tion. Apart from its structural roles, the cytoskeleton
reticulum. Mitochondrial biogenesis also requires is an important participant in many cellular
replication of mitochondrial DNA (mtDNA) and processes, including signal transduction.
synthesis of additional mitochondrial membranes. The cytoskeleton is constructed from three
Degradative pathways control the levels of mito- types of fibers: microfilaments, microtubules,
chondria and mitochondrial proteins. Damaged and intermediate filaments. These proteins are
mitochondrial fragments are engulfed by au- long strings of monomers connected end-to-end
tophagosomes and degraded in lysosomes. Cells to form a polymer. Microtubules are large, stiff
that fail to destroy defective mitochondria suffer tubes composed of the protein tubulin. Micro-
energy shortfalls and eventually cell death. filaments are small, flexible chains of actin. Inter-
mediate filaments, so named because they are
intermediate in size, are composed of many types
The cytoskeleton controls cell shape and of monomers. Most cells possess each of these cy-
directs intracellular movement toskeletal elements, but many cells are richer in
The cytoskeleton is a network of protein-based one particular type. For example, the tails of sperm
fibers that extends throughout the cell (Figure 53). are largely microtubules, muscles are largely actin

Chemistry, Biochemistry, and Cell Physiology

Mitochondrial reticulum



Outer Inner membrane Mitochondrial Microfilaments

membrane cross-section (red)



Contact site

Figure 52 Mitochondrial structure Mitochondria are

found in almost every cell type, but with many different
appearances. Muscle mitochondria exist as a network
extending throughout the muscle myofibrils. In cross-section
they appear as individual organelles, but three-dimensional Nucleus
reconstructions show the reticulum structure. Inside the
mitochondria the highly folded inner membrane can be seen.

polymers, and skin is rich in the intermediate fila- filaments
ment keratin.
Other proteins work in conjunction with the
cytoskeleton to conduct many types of movement.
These proteins, called motor proteins, are
mechanoenzymes that use the energy of ATP hy-
drolysis to walk along the cytoskeleton. Myosin is
the motor protein that walks along actin polymers;
kinesin and dynein move on microtubules. (b)
Figure 53 Three protein fibers of the
The endoplasmic reticulum and Golgi cytoskeleton Panel (a) shows microtubules (green) and
microfilaments (red). Panel (b) shows intermediate filaments.
apparatus mediate vesicular traffic
Cells have layers of membranous organelles extend-
ing around the nucleus to the periphery of the cell help form the vesicle, but they also have an impor-
(Figure 54). The first layer, the endoplasmic retic- tant influence on where the vesicle is sent.
ulum (ER), is the gateway to the other compart- Cells are often illustrated in ways that suggest
ments. Proteins are made in the ER, folded, and that vesicles drift freely throughout the cyto-
then sent to their final destinations in the plasma plasm. In reality, vesicles are carried throughout
membrane, the Golgi apparatus, lysosomes, and en- the cell by motor proteins moving on cytoskeletal
dosomes. The vehicle that carries proteins between tracks. For example, vesicles coated with COP-I
compartments is a vesicle, a small membrane- may be carried toward the Golgi apparatus,
bound organelle. Some vesicles are surrounded by whereas vesicles coated with COP-II may be sent
a shell of coat proteins, such as clathrin, coat pro- to the ER. Coat proteins and other vesicle mem-
tein complex I (COP-I), and COP-II. These proteins brane proteins influence which motor protein is

Chemistry, Biochemistry, and Cell Physiology

Damaged mitochondrion Cytoplasm Extracellular fluid

Autophagosome Lysosome

Late endosome



Endoplasmic Golgi
reticulum network

Figure 54 Intracellular traffic Vesicles move throughout the cell, transferring

membranes and vesicle contents between compartments.

bound. If a vesicle binds myosin it will be carried Conversely, when a secretory vesicle fuses to the
on microfilaments, but if it binds dynein it will be plasma membrane, its internal contents are ex-
carried on microtubules. Protein kinases and pelled but the vesicle membrane, both lipid and
protein phosphatases regulate vesicular traffic by integral proteins, disperses into the plasma mem-
altering the cytoskeleton, motor proteins, or vesi- brane. Cells control the numbers and types of pro-
cle proteins. These processes ensure that vesicles teins in the plasma membrane through endocytosis
and their contents are sent to the correct location and exocytosis. Vesicles rich in transporters fuse to
at the correct time. the plasma membrane to increase transport capac-
Many types of intracellular sorting pathways ity. Conversely, regions of the plasma membrane
use the ER-Golgi network. Most cells produce pro- are extracted during vesicle formation to remove
teins, and sometimes other molecules, for release transporters for storage or degradation. Vesicles in
from the cell. This process, called exocytosis, be- transit can be directed to other compartments to
gins in the ER. Proteins are made here and pack- assist in processing their contents. Endosomes act
aged into vesicles that move through the Golgi as clearinghouses for vesicles, collecting them and
apparatus, ultimately fusing to the plasma mem- then redistributing their contents and membrane
brane to release the vesicle contents to the extracel- proteins into new vesicles that are sent to their cor-
lular space. In the reverse pathway, endocytosis, rect locations. They send damaged proteins and
vesicles form at the plasma membrane, engulfing foreign materials to lysosomes for proteolytic
liquid droplets (pinocytosis) or large particles degradation. Once vesicles reach their destination,
(phagocytosis). The same pathways of endocytosis another series of proteins mediate the fusion of
and exocytosis regulate the proteins found in the vesicles with target membranes.
plasma membrane, such as membrane trans- The pathways of intracellular sorting allow
porters and channels. When transporters are no animal cells to control many of the processes we
longer needed, they can be removed from the mem- have considered throughout this chapter, includ-
brane and stored in vesicles until needed again. ing secretion, ingestion, and membrane transport.

Chemistry, Biochemistry, and Cell Physiology

Another function of these pathways, Proteins and glycoproteins

specifically the secretory pathway, is
to build and maintain a fibrous net- Simple structures Complexes

work outside the cells: the extracel- Carbohydrate Collagen monomes Cross links
lular matrix. Collagen

The extracellular matrix Elastin
mediates interactions between
cells Collagen
Cells are organized into a three-
dimensional tissue by a network of Heparin
fibers called the extracellular ma-
GAGs and proteoglycans
trix. The proteins used to build the
matrix are synthesized by the ER, Simple structures Complexes
packaged into vesicles, and sent out
of the cell using the secretory path-
way. During transit through the Golgi Hyaluronan
apparatus, suites of enzymes modify Aggrecan
the proteins, adding branched chains Core protein Keratan sulfate aggregate
of sugars. As you learned earlier in
this chapter, glycosylation alters the
properties of the proteins in many
Chondroitin sulfate Aggrecan
ways. In the extracellular matrix, wa-
ter binds to the hydrophilic sugars to Figure 55 Extracellular matrix components The extracellular matrix is
create a gel-like coating that fills the composed of combinations of proteins and glycoproteins, glycosaminoglycans (GAGs)
space between cells. and proteoglycans. Many of the individual molecules, shown in the left column, can be
Extracellular matrix macromol- combined into more complex macromolecules, shown on the right. The protein
ecules can be proteins, simple gly- components are shown in green and the GAG components in blue.
coproteins, glycosaminoglycans, or
combinations of both, known as proteoglycans lently attached to proteins to form proteoglycans.
(Figure 55). Collagen is a long, stiff fiber formed Cartilage is composed primarily of aggrecan, a
as a triple helix of three separate collagen glyco- proteoglycan that incorporates more than 100 gly-
protein monomers. Elastin is a small protein that cosaminoglycans into its structure. Many proteo-
is linked together into an intricate web. When the glycans link the different extracellular matrix
network is stretched it acts like a rubber band, proteins together to form a network.
providing the tissue with elasticity. Many extracel- The extracellular matrix can be simple in
lular matrix components are linked together by structure and composed of only a few proteins, or
the glycoprotein fibronectin. Each fibronectin mol- it can be organized into an extensive network. The
ecule binds other fibronectins as well as different extracellular matrix is more than just the cement
matrix components to form a fibrous network. that connects cells together. Many specialized
Hyaluronan is a glycosaminoglycan composed structures such as the insect exoskeleton, verte-
of thousands of repeats of the disaccharide glu- brate skeleton, and molluscan shells are modified
curonic acid-N-acetylglucosamine. With its hydra- extracellular matrices secreted by specific cells.
tion shell, it forms a noncompressible gel that acts For example, bone and cartilage are tissues
as a cushion between cells. Hyaluronan fills the formed from the extracellular matrix of os-
spaces between joints of land animals, easing teoblasts and chondroblasts, respectively. The
movement. Other glycosaminoglycans, such as basal lamina (Figure 56), or basement mem-
2 brane, is a type of extracellular matrix found in
chondroitin sulfate and keratan sulfate, are cova-
many tissues, where it acts as a solid support that
Keratan is a GAG of the extracellular matrix, whereas keratin helps anchor cells. It is designed and maintained
is an intermediate filament protein of the cytoskeleton. primarily by specialized cells called fibroblasts.

Chemistry, Biochemistry, and Cell Physiology

Epithelial cell

Connective tissue:


Blood vessel Plasma

membrane Collagen Proteoglycans Membrane

Figure 56 Basal lamina In many tissues, fibroblasts produce a thick layer of

extracellular matrix called the basal lamina. Some cells use the basal lamina as a foundation,
but other cells and blood vessels use it as a porous frame.

Cells use various strategies to modulate both trix metalloproteinases to break down the extra-
the matrix properties and their relationship with cellular matrix of the local cells to allow the blood
the matrix. First, most types of extracellular ma- vessels to penetrate into new regions of the tissue.
trix components can be made many ways. For in-
stance, mammals have 20 different collagen
genes, so in principle a collagen trimer can be con-
structed 8000 (203) ways. Even though most of
Physiological Genetics
these possible variants are never constructed, it il-
and Genomics
lustrates the potential for variation in one of the The nature of physiological diversity, whether in
many components of the extracellular matrix. Sec- the response of an individual or in the variations
ond, variations occur in the type and position of arising over evolutionary time, resides in the
carbohydrate groups of simple glycoproteins and genes: how they differ between species and how
proteoglycans. Each variation influences the phys- they are regulated in individual cells. Homeostatic
ical properties of the extracellular matrix protein. regulation depends on the ability of the cell to put
By controlling which proteins are made and how the right protein in the proper place at the proper
they are modified by glycosylation, cells determine time with the appropriate activity. Cells have many
which building blocks are available to build the ex- mechanisms to control the rates of synthesis of
tracellular matrix. Cells control which proteins are specific proteins. RNA polymerases read the
released to the extracellular space using the secre- genes, producing mRNA in the process of trans-
tory pathway discussed in the previous section. cription. Once RNA is made, it is used as a tem-
Secreting the extracellular matrix components plate to produce protein in the process of
from the cell is really only one step in building a tis- translation. Cells can control the levels of both
sue. The cells also produce integral membrane RNA and protein using mechanisms that target
proteins called matrix receptors to connect them to rates of synthesis and degradation.
the extracellular matrix. Integrins are an impor-
tant class of plasma membrane receptors that bind
the cytoskeleton on the inside of cells and bind the
Nucleic acids are polymers of nucleotides
extracellular matrix on the outside of cells. A cell The two types of nucleic acids, deoxyribonucleic
changes its association with the extracellular ma- acid (DNA) and ribonucleic acid (RNA), are struc-
trix by changing the types of integrins in its mem- turally similar but perform different functions
brane, mediated by endocytosis and exocytosis. within the cell. DNA is the genetic blueprint for
Cells can also break down the extracellular building cells. RNA reads the information encoded
matrix by secreting proteases called matrix metal- by the DNA and interprets it to make proteins.
loproteinases. By controlling both the production Cells produce three main forms of RNA: transfer
of the matrix and its degradation, cells can regu- RNA (tRNA), ribosomal RNA (rRNA), and messen-
late their ability to move throughout a tissue. For ger RNA (mRNA). Certain molecules of RNA com-
example, when blood vessels grow, they use ma- plex with proteins to form riboproteins.

Chemistry, Biochemistry, and Cell Physiology

Both RNA and DNA are polymers of nu- Double-stranded DNA twists into an
cleotides. All nucleotides are composed of a ni- with two topological features: a minor groove and
trogenous base attached to a sugar linked to a a major groove. The two strands of DNA appear as
phosphate. RNA and DNA differ in the type of ridges, separated by a trough. These contours be-
sugar in the nucleotide: ribonucloetides contain tween two strands compose the minor groove. The
ribose whereas deoxyribonucleotides possess major groove results from the twisting pattern of
deoxyribose. Both RNA and DNA are synthesized the
-helix. Every 10 base pairs, a distance of
from combinations of four types of nucleotides about 3.6 nm, the helix completes a full turn,
that differ in the nature of their nitrogenous bases. forming the major groove that resembles a saddle.
Three of the four nitrogenous bases, the pyrimidine Variations in nucleotide sequence cause subtle re-
cytosine and the purines adenine and guanine, are gional alterations in the shape of DNA and the
found in nucleotides of both RNA and DNA. The topology of the major and minor grooves. This
fourth nitrogenous base is another pyrimidine: structural variation is information that is used by
uracil in RNA and thymine in DNA. The ribonu- the DNA-binding proteins to attach to the correct
cleotides are ATP, UTP, CTP, and GTP. The deoxyri- location to regulate expression of specific genes.
bonucleotides are dATP, dTTP, dCTP, and dGTP. In The DNA in animal cells is highly compressed
many cases, the nucleotide sequence in DNA and into tight structures with the aid of DNA-binding
RNA is represented using one-letter codes. Thus, A proteins called histones. If you were to unwind
refers to the residue derived from the nucleotide the DNA in a single mammalian cell, the strands
ATP (in RNA) or dATP (in DNA), C is CTP/dCTP, G is would stretch several meters. The long strands of
GTP/dGTP, T is dTTP, and U is UTP. DNA wrap twice around the barrel-shaped his-
Nucleic acids form from long polymers of nu- tones until a structure resembling a strand of
cleotides linked by phosphodiester bonds that form pearls is formed. These strands are then twisted
between the phosphate of one nucleotide and the and folded into highly compressed arrangements,
sugar of the adjacent nucleotide. The end of the poly- which has two main advantages to cells. First, it al-
mer that terminates with a phosphate group is lows the cell to fit large amounts of DNA into the
deemed the 5-prime end (5′); the other end termi- small volume. Second, coating DNA with histones
nates with a sugar and is the 3′ end. The nucleic acid helps reduce the damage caused by radiation and
has a polarity, conferred by its 5′ and 3′ ends, that is chemicals. However, in this compressed configura-
an important consideration when discussing the bio- tion DNA is biochemically inert; it cannot function
chemical processes involved in nucleic acid function. as a template for RNA synthesis (transcription)

DNA is a double-stranded
packaged into chromosomes
DNA usually exists within cells as a 3′ 5′
double-stranded polymer (Figure 3′
C Nucleotide Minor
57) in which hydrogen bonds connect G
the two strands. Each specific nu- Phosphate
cleotide can form hydrogen bonds
with only one other nucleotide. Three G C (deoxyribose) Major
hydrogen bonds form between G and groove

C, whereas two hydrogen bonds form T A Sugar-

between A and T. When one strand of Hydrogen phosphate
3′ bonds backbone
DNA encounters another comple- 5′
mentary strand, hydrogen bonds 3′ 5′
form between the strands, creating a (a) Schematic model (b) Ribbon diagram (c) Space-filling model
double-stranded molecule. The two Figure 57 DNA structure Each strand of DNA binds to another,
strands anneal in an antiparallel complementary strand. Hydrogen bonds form between specific base pairs. Two bonds
arrangement, with the 5′ end of one form between A and T. Three bonds form between C and G. The double-stranded DNA
strand associated with the 3′ end of is twisted into an
-helix, forming a minor groove between strands. The major groove
the other strand. reflects the period of the twisting of the helix.

Chemistry, Biochemistry, and Cell Physiology

or DNA synthesis (replication). Cells must use tionship between the size of the genome and the
histone-modifying enzymes to release histones complexity of the animal. For example, both the
from DNA, thereby regulating gene expression. largest and the smallest vertebrate genomes are
found in fish. The pufferfish genome is only about
DNA is organized into genomes 0.3% the size of the lungfish genome. There is also
no relationship between the number of chromo-
The entire collection of DNA within a cell is called somes and the complexity of the animal. Humans
the genome. Within the nucleus, the genome is di- possess 46 chromosomes. Some deer have only 6,
vided into separate segments of DNA called whereas carp may have more than 100.
chromosomes. Within chromosomes are the
genes, which possess the DNA sequences that are
used to produce all the different types of RNA, in- Transcriptional control acts at gene
cluding the mRNA that encodes proteins. Each regulatory regions
gene also possesses regions of DNA called promot- The rate of synthesis for many proteins is propor-
ers that determine when the gene is expressed. tional to the levels of mRNA. Historically, mRNA
Many genes are divided into multiple sections on
the same chromosome. The sections that encode Mammals
RNA are known as exons, and the interspersed
DNA sections are called introns (Figure 58).
In most animals, genes account for less than Reptiles
half of the genome. The majority of the genome is Frogs
a mixture of different types of random and repeti- Salamanders
tious DNA, much of which serves no known func-
tion and is often called junk DNA.
Across the animal kingdom, genome size Teleosts
ranges more than 6000-fold (Figure 59). The small- Chondrichthians
est genome is found in one of the simplest animals; Agnathans
placozoans, a relative of sponges, have only about Nonvertebrate
0.02 pg of DNA per cell. The largest genome in an-
imals, about 133 pg/cell, belongs to the African Crustaceans
marbled lungfish. Surprisingly, there is little rela- Insects

Centromere Molluscs

(a) Chromosome Flatworms


Exons 10–2 10–1 1 10 102 103
Genome size (pg)
Gene Figure 59 Genome sizes in the animal
(b) Gene
kingdom The genome size in animals can vary widely,
Figure 58 Chromosomes and genes Chromosomes and there is no relationship between genome size and
possess structural regions, such as centromeres and telomeres, complexity. Bar lengths reflect the range in the sizes of
in addition to noncoding regions and genes. genomes measured in picograms (pg).

Chemistry, Biochemistry, and Cell Physiology

levels were measured using northern blots, but re- Cells can regulate the rate of mRNA synthesis
cent advances in genomics and engineering have by altering the conformation of the gene and
led to the development of techniques for assessing changing the ability of the transcriptional machin-
complex changes in the levels of mRNA for thou- ery to assemble. Sometimes gene expression is in-
sands of genes simultaneously. duced by stimulation of the enzymes that remodel
At any point in time, most of the genome of a chromatin. These enzymes work by altering the
cell is wrapped around histones and rolled into nu- structure of the histones that organize DNA into
cleosomes (Figure 60). Under these conditions the nucleosomes. Histones can be modified by acety-
genes are quiescent, unable to bind the transcrip- lation, methylation, and phosphorylation. For ex-
tional machinery. When the gene product is re- ample, when a histone acetyl transferase (HAT)
quired, the chromatin must be remodeled to allow adds an acetyl group to a critical lysine in a his-
transcriptional activators access to the regulatory tone, this induces a change in structure that per-
regions of the gene. Transcriptional regulators, mits remodeling of chromatin to favor gene
both DNA-binding proteins and coactivators, asso- expression. The gene can be silenced by a histone
ciate with each other to form regulatory complexes deacetylase (HDAC) that removes the acetyl group.
on the promoter. The transcription initiation com- Once the regulatory regions within the gene
plex assembles near a specific region of the pro- are exposed, the transcriptional machinery is
moter designated as the transcription start site, able to assemble. Transcription factors may bind
typically a sequence of TATA (the TATA-box). Once to sites close to, or distant from, the transcrip-
the complex assembles, the process of mRNA syn- tional start site. Some transcription factors intro-
thesis can begin. duce bends into the DNA that bring critical
regions of the gene in close proximity. Other tran-
scription factors bind coactivators, which serve
as docking sites for other proteins. Eventually,
the general transcription factors are assembled,
the RNA polymerase is recruited, and the process
of transcription can begin. The entire process de-
pends critically on the interactions between
dozens of proteins. Consequently, cells can fine-
Histone tune the process by regulating the ability of dif-
Histone remodeling
ferent proteins to interact, typically by changes in
Histone protein phosphorylation. The phosphorylation
state can affect the transfer of a transcription fac-
tor between the cytoplasm and the nucleus. It can
also alter the ability of transcriptional regulators
regulators bind to interact with DNA or other proteins, both stim-
ulatory and inhibitory proteins. Since each gene
is regulated by dozens of transcription factors,
the combinations of regulatory conditions are
transcription The primary mRNA transcript possesses se-
factors quences that will eventually code for the protein
(exons) as well as other sequences that are inter-
start site RNA polymerase spersed between exons (introns). It must first be
processed in a way that removes introns and
Figure 60 Transcriptional regulation Quiescent
splices together exons. Next, the spliced RNA must
DNA is tightly wrapped around histones. Remodeling of
be polyadenylated; long strings of 200 or more
chromatin gives DNA-binding proteins access to gene
control regions. The general transcription factors allow RNA ATP residues are added to the 3′ end of the tran-
polymerase II to bind to initiate transcription. Other DNA script to produce the poly A tail that is character-
regulatory proteins, such as the activators and coactivators istic of mRNA. Once these post-transcriptional
shown here, increase the likelihood that the transcriptional modifications are completed, the mature mRNA is
machinery will assemble. exported to the cytoplasm.

Chemistry, Biochemistry, and Cell Physiology

RNA degradation influences RNA levels called a codon. The 5′ end of the mRNA recruits
proteins called initiation factors, in combination
Controlling transcription is one important mecha-
with a methionine tRNA (tRNAMET) and a ribo-
nism for cells to alter RNA levels; another is to vary
some. The complex moves down the mRNA chain
the rate of RNA degradation. RNA is degraded by
until it reaches the sequence AUG, which is the
nucleases called RNases. An RNase can attack the
start codon. Another amino acyl tRNA is recruited,
end of the RNA (exonucleases) or internal sites
and the ribosome catalyzes the formation of a
(endonucleases), preventing the mRNA from act-
peptide bond between the amino acids to begin
ing as a template for protein synthesis.
the process of elongation. In most circumstances,
Cells have ways to preferentially degrade or
proteins called elongation factors enter the ribo-
protect individual mRNAs. A long poly A tail pro-
some and accelerate the catalytic cycle. In a typi-
tects an mRNA from degradation. Soon after re-
cal animal cell, each individual ribosome can add
lease into the cytoplasm, exonucleases nibble off
an amino acid to the chain at a rate of one to two
the ends of the poly A tail. The mRNA can still be
per second. The process continues until the ribo-
translated into protein at this point. Once the
somal complex reaches a stop codon, a nucleotide
exonucleases shorten the tail to about 30 bases,
sequence that is incapable of binding any amino
the RNA is attacked by an endonuclease, causing
acyl tRNA. At any point in time, a single mRNA
enough damage to prevent the protein from being
may be translated by many ribosomes bound all
along the mRNA.
Other processes accelerate the rate of mRNA
Cells can control the rate of translation using
degradation. Some mRNAs are unstable, existing
nonspecific mechanisms that affect all translation
in the cytoplasm for only a few minutes before be-
within the cell, as well as specific mechanisms that
coming degraded. These unstable mRNAs have
influence only a subset of mRNAs. Many of the ini-
long stretches of A and U bases within their 3′ un-
tiation factors and elongation factors are regulated
translated regions (3′ UTR). These AU-rich regions
through protein phosphorylation. In addition,
recruit proteins that accelerate mRNA degrada-
each of these factors can bind inhibitory proteins.
tion. The ability to accelerate RNA degradation is
Such mechanisms allow cells to mount global
essential in many cells, particularly those that pro-
changes in translation rates. Many types of mRNA
duce regulatory proteins. Once a signaling protein
possess sequences that act to regulate their trans-
is no longer needed, the RNase machinery can
lation. For example, sequences in the 3′ UTR and
rapidly degrade the mRNA to prevent it from be-
5′ UTR bind proteins that alter the ability of the
ing translated.
mRNA to be translated.
Cells can also reduce the rate of RNA degrada-
tion. Stabilizing proteins can bind to specific re-
gions in the poly A tail or other regions of the Cells rapidly reduce protein levels through
mRNA to prevent RNase attack. This allows the protein degradation
cell to maintain a pool of preformed mRNA avail-
Once proteins are synthesized, they remain in the
able for immediate use if cellular conditions de-
cell until they are degraded. Just as cells use
mand the gene product.
degradation to control mRNA levels, they use pro-
tein degradation to control protein levels. Some
proteins are removed only when they sustain
Global changes in translation control many enough damage to become dysfunctional. The
pathways structural changes in damaged proteins recruit
Once an mRNA arrives in the cytoplasm, the enzymes that mark the protein for degradation.
process of translation can begin with the assis- These enzymes transfer a small protein called
tance of ribosomes and amino acyl tRNAs. Ribo- ubiquitin to the damaged protein. Once the
somes, complexes of rRNA and proteins, catalyze ubiquitination machinery has attached a ubiquitin
the formation of peptide bonds between amino chain to the damaged protein, the protein is
acids in the growing protein. The amino acids are bound by a multiprotein complex called the
provided in the form of amino acyl tRNA. Each proteasome. Proteolytic enzymes within the pro-
amino acid uses a specific tRNA that can bind to a teasome degrade the ubiquitin-tagged proteins to
specific set of three nucleotides on the mRNA amino acids.

Chemistry, Biochemistry, and Cell Physiology

Earlier we discussed how some types of mRNA Primary transcript E1 E2 E3 E4 E5 E6

are preferentially degraded. Many of these unsta- E1 E2 E3 E4 E5 E6 E1 E3 E4 E5 E6
ble mRNAs encode proteins that are also subject to E1 E3 E5
accelerated degradation. Proteins such as cell cy-
cle regulators and transcription factors can be
ubiquitinated even in the absence of structural
damage. Characteristic amino acid sequences
within the proteins recruit the ubiquitination ma-
(a) Alternate splicing
chinery. Often the recognition sequences can be
phosphorylated, altering their ability to be sub-
jected to rapid degradation. LDH-A
Collectively, cells use these regulatory LDH-a
processes to control the levels of mRNA and pro-
tein. They enable cells to modify cellular proper-
ties in response to changing environmental and
physiological conditions. Cells are also able to
modulate their physiological response by altering
the types of proteins they express. Animals, partic-
1 1
ularly vertebrates, can draw upon isoforms of pro-
teins with subtly different properties that provide (b) Allelic variation

cells with alternative strategies to meet environ-

mental and physiological challenges.
Protein variants arise through gene
duplications and rearrangements
Protein isoforms provide a cell with flexibility in
structure and function. A suite of proteins can be
created with distinct properties. Isoforms can be
produced through multiple mechanisms involving (c) Gene families
single genes, different alleles, or different genes Figure 61 Origins of protein variants Cells are
(Figure 61). able to produce protein isoforms in many different ways.
Variations in protein structure can arise when Cells can splice exons in different combinations to create
the primary mRNA from a gene is connected to- distinct proteins. Often the same gene can occur in different
gether using different combinations of exons, a sequences within a population. Some individuals can have
process known as alternative splicing. For ex- two different versions of the same gene (A or a) on
ample, more than 40 different isoforms of fi- chromosomes inherited from each parent. Gene duplications
can lead to extra gene copies in different loci. These genes
bronectin can result from a single gene. Each
can diverge to encode different enzymes (A and B).
isoform of fibronectin binds different combina-
tions of extracellular matrix molecules.
Within any population of animals, there is
some variation in the exact sequence of specific or catalytic properties of allozymes may be subtly
genes. As a consequence, a diploid individual may different. Often different allozymes predominate
possess two different versions of the same gene, in two populations of animals. For example, if a
one arising from the mother and one from the fa- specific allozyme functions better in the cold, that
ther. These different forms of the same gene are gene might occur at a higher frequency in popula-
alleles. If the gene encodes an enzyme, the iso- tions of animals exposed to the cold.
forms are also called allozymes. Often the differ- Other types of isoforms are encoded by sepa-
ences in allozyme structure have little effect on rate genes that arose from ancestral gene dupli-
function. Because they are functionally neutral, cations. Figure 62 shows some of the ways that
natural selection does not remove them from the genes can become duplicated. During the
population. However, in some cases the regulatory process of meiosis, long stretches of DNA may be

Chemistry, Biochemistry, and Cell Physiology

will be endowed with extra copies of the dupli-

cated genes. These extra copies could kill the cell
or, if neutral or beneficial, get transmitted to the
next generation.
Another way that genes can become dupli-
cated is through mobile elements. Many organ-
isms possess genes that are capable of jumping
from one chromosome to another. In most cases,
the mobile element encodes a transposase, the en-
(a) Homologous recombination zyme required to cut the DNA from one strand and
(equal crossover)
insert it into another. Occasionally, other genes be-
come trapped in the mobile elements. When the
mobile elements move, the other genes are carried
along, endowing the recipient chromosome with
the extra copy.
Genetic recombination does not always lead to
production of extra copies of entire genes. In some
cases, fragments of genes are moved from one
gene and inserted into a completely different gene.
A protein may possess domains within its struc-
(b) Unequal crossover ture that resemble regions of otherwise unrelated
proteins. For instance, hundreds of different pro-
teins can bind ATP using a protein structure called
an ATP-binding cassette. This structure, which
appears in all living organisms, probably arose
only once, or a few times, billions of years ago. Its
appearance in so many different genes and in all
taxa is likely due to genetic recombination events
that moved this region from one gene to another.

(c) Mobile elements Ancient genome duplications contribute

to physiological diversity
Figure 62 Gene duplications Gene recombination
can provide cells with extra copies of genes. In contrast to Gene duplications provide organisms with extra
equal crossover, (a) where homologous regions of copies of redundant DNA that can accumulate mu-
chromosomes are exchanged, unequal crossover (b) provides tations and diverge to endow the organisms with
one chromosome with extra genetic material. (c) Cells also novel capacities. The key to achieving the oppor-
possess many different kinds of mobile elements that can tunity for specialization is obtaining the raw mate-
move or duplicate genes between chromosomes. rial: a nonlethal extra copy of a gene. At several
points in the evolution of animals, whole genomes
transferred from one chromosome to another. In were duplicated. Many of the duplicated genes
most cases, two chromosomes exchange homolo- were eventually lost, but many were retained and
gous regions and no gain or loss of genes occurs. diverged to form gene families. Many of the
This process of shuffling gene combinations is anatomical and functional specializations of verte-
one of the advantages of sexual reproduction. Oc- brates are a result of these genomic duplications.
casionally, the machinery of homologous recom- Often, if a particular gene is found in a single
bination misidentifies homologous regions. copy in an invertebrate, there are four isoforms in
Unequal crossover results, and one chromosome vertebrates. This “rule-of-four” reflects ancestral
donates an end to another chromosome. The genome duplications; each single gene locus was
progeny derived from the gamete that lost the duplicated, giving two copies of all genes, then
chromosomal region would not likely survive. reduplicated, giving four copies of all genes. The
However, the progeny from the recipient gamete individual genes within the duplicated genomes

Chemistry, Biochemistry, and Cell Physiology

underwent mutation, selection, and drift to di- verged in structure, they have not yet become dif-
verge into distantly related genes. After a period of ferent in function.
divergence, some individual genes duplicated Over many generations, the duplicated genes
again. The newly duplicated genes were more can follow many fates. The duplicated gene might
closely related to each other than to their distant incur mutations in the promoter or coding region
ancestors, creating gene clusters. When did these that prevent it from being transcribed, rendering
genome duplications occur? A possible answer it a pseudogene. In some cases, one copy of the
comes from phylogenetic analyses of a family of gene mutates and diverges, resulting in a protein
genes involved in development, the Hox family. with distinct properties. In other cases, both
The first genome duplication probably occurred copies mutate and diverge, resulting in a pair of
just before the jawless vertebrates, or agnathans, proteins with overlapping functions.
diverged from the vertebrate lineage. The second These genetic processes, originating early in
duplication coincided with the development of animal evolution and operating at the level of indi-
jaws. The primitive chordates such as amphioxus vidual cells, provide animals with physiological
have a single cluster of Hox genes, the agnathan flexibility. The integration of different cell types
lamprey has two or sometimes three clusters, and into complex physiological systems is an impor-
the more recent jawed vertebrates, from sharks to tant reason why animals have radiated into so
humans, possess at least four clusters of Hox many diverse species over the course of evolution.
genes. In each case, genome duplications coin-
cided with important revolutions in morphological
and physiological complexity. 2 C O NC E P T C H E CK
These original genome duplications in the ver-
13. Compare the categories of membrane transport
tebrate lineage probably occurred more than 300 in terms of energy requirements and direction of
million years ago. Many modern animals have ex- transport in relation to chemical gradients.
perienced relatively recent genome duplications, 14. Discuss the composition of biological
including many examples of frogs and fish that membranes. What are the unique properties of
gained an extra set of chromosomes to become each type of lipid?
tetraploids. In some cases, tetraploid populations 15. How can cells alter the fluidity of membranes,
exist within diploid species; not nearly enough and why is this capacity important to cellular
time has passed within the tetraploid lineage for function?
the duplicated genes to diverge. The common 16. Summarize the roles of the different subcellular
compartments within a cell, and discuss how
carp, however, became tetraploid about 15 million
they influence physiological function.
years ago. Its closest relative, the grass carp, has
17. Discuss the origins of genetic variation. How
half the number of chromosomes. Many genes that
does genetic variation provide physiological
are in single copy in other vertebrates are found in flexibility?
pairs in common carp. While the pairs have di-

Chemistry k Cells can also store energy in the form of elec-
k All biological systems depend on kinetic and po- trochemical gradients. Gravitational energy and
tential energy. elastic storage energy are used in locomotion.

k Food webs are essentially transfers of chemical k Covalent bonds, which arise when two atoms
energy between organisms. share electrons, are strong in comparison to
weak bonds, including hydrogen bonds, van der
k Molecules possess thermal energy, which is re-
Waals forces, and hydrophobic interactions.
flected in molecular movement, and many
metabolic processes in cells are mechanisms for k Weak bonds control the three-dimensional struc-
capturing and transferring this energy. ture of macromolecules. They form and break in
response to modest changes in temperature.

Chemistry, Biochemistry, and Cell Physiology

k Solute concentration imposes osmotic chal- branes. Steroids and their precursors fulfill
lenges. Organisms must modulate their biologi- many roles within cells, and steroid hormones
cal solutions to regulate the ionization of water are particularly important in cell signaling.
into H and OH.
k Cells oxidize fatty acids for energy using the mi-
k Changes in proton concentration, or pH, alter tochondrial -oxidation pathway, which gener-
many molecular properties. As a result, animals ates reducing equivalents and acetyl CoA. The
have many physiological mechanisms to regu- rate of -oxidation is governed by the availabil-
late pH, including pH buffers. ity of fatty acids and the rate of transport into
the mitochondria using the carnitine shuttle.
k Enzymes are organic catalysts, usually pro- k Fatty acids can be synthesized by the enzyme
teins, that speed reactions by reducing the acti- fatty acid synthase, for use in biosynthesis or
vation energy barrier. energy storage. When energy is needed, lipases
can break down triglycerides to release the
k Enzyme reaction velocity (V) and substrate fatty acids.
affinity (Km) depend on the physicochemical en-
vironment, such as the temperature, ion com- k Under some conditions, such as starvation, fatty
position, and pH of the solution. acids can be converted to ketone bodies for use
in tissues that cannot use fatty acids directly.
k Cells control reaction rates by changing the con-
centration of reactants, the levels or activities of k Most oxidative fuels can be converted to acetyl
enzymes, or the concentration of substrates and CoA within mitochondria. When acetyl CoA en-
products. ters the tricarboxylic acid cycle, acetyl CoA is
oxidized to produce reducing equivalents,
k Competitive inhibitors compete for the enzyme NADH and FADH2.
active site. Allosteric regulators bind at loca-
tions distant from the active site, altering en- k Oxidation of reducing equivalents by the elec-
zyme kinetics. Many enzyme and nonenzyme tron transport system generates a proton gradi-
proteins are regulated by covalent modification. ent, heat, and reactive oxygen species.
For example, protein kinases use ATP to attach
k The mitochondria F1FO ATPase, or ATP syn-
phosphate groups to specific amino acid
thase, uses the proton motive force to generate
residues, and protein phosphatases remove
ATP. Phosphorylation is coupled to oxidation
phosphate groups.
through a shared dependence on the proton
k Cells use combinations of enzymes and enzy- motive force.
matic regulation to construct and maintain
k Under some circumstances, mitochondria can
complex metabolic pathways.
become uncoupled, leading to the production of
k Proteins, carbohydrates, and lipids have impor- heat instead of ATP.
tant roles in structure and metabolism. Animals
k The balance between biosynthesis and catabo-
store excess carbohydrate as glycogen. Glucose
lism is regulated by energetic intermediates
can be produced from noncarbohydrate precur-
such as ATP, NADH, and acetyl CoA. Without
sors using gluconeogenesis. Glucose can be bro-
this regulation, the two processes could occur
ken down to pyruvate (glycolysis) or further
simultaneously, leading to loss of energy in fu-
oxidized to CO2.
tile cycles.
k Most animals use lactate dehydrogenase to bal-
k Metabolic regulation also determines which fu-
ance redox and dispose of pyruvate. Anoxia-
els are oxidized under which conditions.
tolerant animals can use other pathways for
oxidizing NADH in the absence of oxygen, some
Cell Physiology
of which provide additional ATP.
k Membranes allow cells to create permeability
k Phospholipids, including phosphoglycerides barriers that help them to define environments.
and sphingolipids, are used to make cell mem- Membranes are heterogeneous combinations of

Chemistry, Biochemistry, and Cell Physiology

phospholipids, cholesterol, and numerous inte- are the most important component of the rest-
gral and peripheral proteins. ing membrane potential. Changes in membrane
permeability alter the membrane potential in
k The nature of the lipid membrane influences
ways that cells use to communicate.
fluidity, an important determinant of protein
function. k Many aspects of animal physiology can be
traced back to cellular processes.
k While some hydrophobic molecules can cross
membranes by passive diffusion, membrane k The basic structure of cells—including the mito-
proteins are required for transport of most chondria, cytoskeleton, extracellular matrix,
molecules. and secretory networks—can be regulated and
remodeled to serve many purposes.
k Some transporters, such as ion channels, facili-
tate the diffusion of impermeant molecules k The ability to follow developmental programs,
down concentration gradients by creating pores. or respond to physiological and environmental
challenges, resides in the genes. Physiological
k Active transporters use energy to pump mole-
change begins in many cases with the ways
cules against gradients.
cells control genes.
k The electrochemical gradients that exist across
k Cells and tissues are remodeled using processes
cellular membranes are produced by active
from transcriptional control to post-translational
transporters and used to drive diverse physio-
logical processes.
k Evolutionary processes, including gene and
k The interior of the plasma membrane is elec-
genome duplications, provide the raw material
tronegative, with a membrane potential be-
for achieving physiological diversity.
tween 5 and 100 mV. Potassium gradients

Review Questions
1. How does the density of water change in rela- 3. What metabolic conditions can affect the val-
tion to temperature? How do these properties ues of the respiratory quotient?
affect animals that live in marine and fresh- 4. What metabolic conditions affect the rela-
water environments? tionship between ATP produced and oxygen
2. If the enzymatic reaction A  B Δ C  D is consumed?
near equilibrium, then the mass action ratio is 5. Trace the path of a protein hormone, such as
close to the equilibrium constant. What hap- insulin, from its gene in the nucleus to secre-
pens to the mass action ratio if you add more tion out of the cell.
enzyme? What happens when you add more
6. Discuss the mechanism by which cells can use
of A? What do you need to know to predict
transporters to change their osmotic and ionic
what would happen if temperature changed?

Synthesis Questions
1. A type of protein comes in six different forms. pyruvate is often close to the Km value for LDH.
Each form can dimerize with the other. How Why might this be advantageous, in terms of
many unique homodimers and heterodimers kinetic regulation?
can be formed from these six proteins? 3. Describe, in chemical terms, how antacids work.
2. Many animals maintain metabolites at con- 4. Why do your hands get wrinkled if you spend
centrations near the Km value for metabolic too much time in the bathtub? Would the same
enzymes. For example, the concentration of

Chemistry, Biochemistry, and Cell Physiology

thing happen when you swim in the ocean? 6. Other physiological processes require changes
Describe these environments using the termi- in the activities of proteins. While this can
nology of osmolarity and tonicity. arise through changes in the levels of pro-
5. Many physiological processes require a teins, it can also change through regulation of
change in the levels of proteins, such as mem- protein function. Discuss the various ways
brane transporters. Discuss the processes that that cells can alter the activity of enzymes or
cells can use to change the protein levels. Dis- transporters.
cuss how the subcellular compartment influ- 7. Discuss the ways in which a cell is able to al-
ences this pathway. ter its interactions with other cells.

Quantitative Questions
1. What is the proton concentration of a solution 3. What rate of oxygen consumption would you ex-
at pH 7.4? At what temperature would this so- pect in a tissue with a metabolic rate of 30 µmol
lution be neutral? ATP/ min?
2. Calculate the basis for an RQ  1 for carbohy-
drate oxidation. Why does palmitate oxidation
give an RQ  0.7?

For Further Reading

See the Additional References section at the end This book looks at how animals and other
of the chapter for more references related to the organisms alter macromolecules in relation to
topics in this chapter. environmental stress.
Hochachka, P. W., and G. N. Somero. 2002.
Chemistry Biochemical adaptation. Oxford: Oxford
These texts provide good overviews of the University Press.
chemical and physical underpinnings of cell
biology and biochemistry. These two books present differing views of the
history of the discovery of the structure of DNA.
Becker, W. M., L. J. Kleinsmith, and J. Hardin.
2003. The world of the cell, 5th ed. San Sayre, A. 1975. Rosalind Franklin & DNA. New
Francisco: Benjamin Cummings. York: Norton, 1975.

Lehninger, A. L., D. L. Nelson, and M. M. Cox. Watson, J. 2001. The double helix: A personal
1999. Principles of biochemistry, 3rd ed. New account of the discovery of the structure of
York: Worth. DNA. New York: Touchstone Books.
This text is a good primer for understanding the
factors that affect protein structure. This book, written by two pioneers in
comparative biochemistry, explores the metabolic
Branden, C., and J. Tooze. 1991. Introduction basis of biological diversity. Although the focus is
to protein structure. New York: Garland on animals, they also consider other organisms
Science. that exemplify biochemical strategies for survival
in adverse environments.
These publications provide good background on
the interactions between energy, chemical bonds, Hochachka, P. W., and G. N. Somero. 2002.
and water. Biochemical adaptation. Oxford: Oxford
University Press.
Bryant, R. G. 1996. The dynamics of water-protein
interactions. Annual Review of Biophysics and Arthur Kornberg’s autobiography gives his
Biomolecular Structure 25: 29–53. perspective on the history of the study of
Thornton, R. M. 1998. The chemistry of life. metabolic biochemistry.
Menlo Park, CA: Benjamin Cummings. Kornberg, A. 1991. For the love of enzymes: The
Westof, E. 1993. Water and biological odyssey of a biochemist. Cambridge, MA:
macromolecules. Boca Raton, FL: CRC Press. Harvard University Press.

Chemistry, Biochemistry, and Cell Physiology

Lehninger is one of the standard undergraduate Ohno’s early book outlines his perspective on the
textbooks in biochemistry, with particularly good importance of gene duplication in the evolution of
sections on metabolism and metabolic regulation. biological diversity. More recently, in a series of
Nelson, D. L., and M. M. Cox. 2000. Lehninger papers, a number of authors bring the field up-to-
principles of biochemistry. New York: Worth. date, incorporating recent evidence of the role of
genome duplications in origins of gene families
Cell Physiology and cellular diversity.
These two textbooks cover the breadth of cell and Ohno, S. 1970. Evolution by gene duplication.
molecular biology, with excellent illustrations. Heidelberg: Springer Verlag.
The strength of Alberts is its comprehensive Various authors. 1999. Gene duplication in
nature, while Becker is very readable. development and evolution. Seminars in Cell
Alberts, B., A. Johnson, J. Lewis, M. Raff, and Developmental Biology 10: 515–563.
K. Roberts, and P. Walter. 2002. Molecular
biology of the cell. New York: Garland Science. An excellent overview of transport and
Becker, W. M., L. J. Kleinsmith, and J. Hardin. transporters.
2002. The world of the cell. San Francisco: Stein, W. D. 1990. Channels, carriers and pumps:
Benjamin Cummings. An introduction to membrane transport. San
Diego: Academic Press.
This comprehensive review of the ATP synthase
does an excellent job of explaining how the The original book by Sir D’Arcy Wentworth
enzyme works in the context of structural models Thompson, written in 1917, was one of the first
of its function. to examine how physiology was influenced by
Boyer, P. D. 1997. The ATP synthase—A splendid mathematics and physics.
molecular machine. Annual Review of Thompson, D. W. 1961. On growth and form.
Biochemistry 66: 717–749. Abridged edition edited by J. T. Bonner.
Cambridge: Cambridge University Press.
This book discusses the nature of evolutionary
and physiological variation from the perspective
of cell and developmental biology.
Gerhart, J., and M. Kirschner. 1997. Cells,
embryos and evolution. New York: Blackwell

Additional References
Benison, S. A., A. C. Barger, and E. L. Wolfe. 1987. Walter B. Madigan, M. T., and B. L. Marrs. 1997. Extremophiles.
Cannon: The life and times of a young scientist. Scientific American 276: 82–87.
Cambridge, MA: Harvard University Press. Maloney, P. C., and T. H. Wilson. 1985. The evolution of ion
Dyson, F. J. 1954. What is heat? Scientific American 191: pumps. BioScience 35: 43–48.
58–63. Mitic, L. L., and J. M. Anderson. 1998. Molecular architecture
Gibbs, A. G. 1998. The role of lipid physical properties in of tight junctions. Annual Review of Physiology 60:
lipid barriers. American Zoologist 38: 268–279. 121–142.
Golding, G. B., and A. M. Dean. 1998. The structural basis of Palmer, T. 1995. Understanding enzymes, 4th ed. London:
molecular adaptation. Molecular Biology and Evolution Prentice Hall/Ellis Horwood.
15: 355–369. Pennycuick, C. J. 1992. Newton rules biology: A physical
Hastings, J. W. 1996. Chemistries and colors of approach to biological problems. New York: Oxford
bioluminescent reactions: A review. Gene 173: 5–11. University Press.
King, J., C. Haase-Pettingell, and D. Gossard. 2002. Protein Powers, D. A., and P. M. Schulte. 1998. Evolutionary
folding and misfolding. American Scientist 90: 445–453. adaptations of gene structure and expression in natural
Kinne, R. K. H., ed. 1990. Basic principles in transport. populations in relation to a changing environment: A
Basel, Switzerland: Karger. multidisciplinary approach to address the million-year
Logue, J. A., A. L. DeVries, E. Fodor, and A. R. Cossins. 2000. saga of a small fish. Journal of Experimental Zoology 282:
Lipid compositional correlates of temperature-adaptive 71–94.
interspecific differences in membrane physical structure.
Journal of Experimental Biology 203: 2105–2115.

Chemistry, Biochemistry, and Cell Physiology

Credits listed in order of appearance.
20 Getty Images, Scott Sady/Getty Images.
21 Photo Researchers, Inc., Eye of Science/Photo
Researchers, Inc.
28 Photo Researchers, Inc., Stephen Dalton/Photo
Researchers, Inc.
75 (a) Dr. Alexey Khodjakov/Photo Researchers, Inc. (b)
Cassiani-Ingoni/Photo Researchers, Inc.

Cell Signaling and Endocrine Regulation
At every level of organization, life depends on communica- into the environment, but its concentration remains low.
tion. Animals send signals to each other in the form of When many bacteria are present within a small area, how-
sounds, scents, and visual cues. Within an animal, organs, ever, the environmental concentration of autoinducer rises.
tissues, and cells communicate with each other using At high concentrations, the autoinducer binds to a specific
chemical and electrical signals. Even within a single cell receptor with the bacterial cell, causing the receptor to
there is constant communication of information among or- change shape and act as a transcription factor that induces
ganelles. Two of the most familiar types of cellular com- the transcription of the genes involved in light production.
munication in animals involve the nervous system and the Thus, when the bacteria are present at high densities, the
endocrine system. Although the nervous and endocrine light-producing genes are induced and the bacteria glow in
systems may appear to be quite different, they are part of the dark.
a continuum of cellular communication systems that share V. fischeri seldom reach high enough densities to glow
many important similarities. when they are free-living, but these bacteria are also found
In all organisms, cellular communication systems in- in a mutualistic relationship with a species of squid—
volve sending and receiving a signal, often in the form of a Euprymna scolopes shown in the photograph above. The bac-
chemical. We can see the fundamentals of these mecha- teria colonize specialized light organs on the underside of
nisms even in prokaryotes. For example, the marine bac- the squid. The squid’s light organs provide an ideal home for
terium Vibrio fischeri is capable of producing light, but does the bacteria, allowing them to grow to very high density and
so only when the bacteria are present at high density. When produce light. This light, which glows from the underside of
the bacteria are at low densities, they produce a chemical the squid, allows the predatory squid to blend in with the
called an autoinducer that diffuses across the membrane light descending through the water from the surface, mak-

From Chapter 3 of Principles of Animal Physiology, Second Edition. Christopher D. Moyes, Patricia M. Schulte.
Copyright © 2008 by Pearson Education, Inc. Published by Pearson Benjamin Cummings. All rights reserved.
The brightly colored rumps of female Hamadryas baboons are the
Aggregation of individual amoeboid cells of Dictyostelium discoideum result of chemical signaling.
into a colony is activated by chemical signals.

entiates to form a complex structure consisting of a stalk

ing them invisible from below. Thus, the glowing bacteria act and a fruiting body. The fruiting body produces spores that
as camouflage that helps the squid to catch their prey. The are capable of surviving extremely harsh conditions. The
complex mutualistic relationship between the bacteria and spores can also break away from the fruiting body to be car-
the squid depends on cellular signaling among the bacteria ried by the wind to other locations. Once conditions improve,
via the autoinducer, and between the bacteria and the squid the spores germinate into individual amoeboid cells, start-
because squid reared in the laboratory in the absence of the ing the cycle over again.
bacteria do not develop a complete light organ. These two examples of cellular signaling, in a prokaryote
Another example of cellular signaling can be found in and a unicellular eukaryote, illustrate the fundamental fea-
unicellular eukaryotes such as Dictyostelium discoideum, a tures of cellular communication in all living things: the pro-
species of cellular slime mold. Much of the time slime duction of a signal in one cell, the transport of that signal to a
molds function as individual, independent, amoeboid cells. target cell, and the transduction of that signal into a response
These cells move through their environment phagocytosing in the target cell.
other cells for food. But when conditions are poor, slime The complexity of animal physiology and behavior re-
mold cells begin to secrete a signaling molecule called quires an enormous diversity in signaling mechanisms.
cyclic adenosine monophosphate (cAMP). When a slime Nowhere is this diversity more obvious than in the endocrine
mold cell encounters environmental cAMP, the cAMP binds system. In most animals, the endocrine system is involved in
to a receptor on the surface of the slime mold cell, causing controlling and regulating almost every physiological
the receptor to undergo a conformational change. The con- process including growth, development, metabolism, and
formational change of the receptor activates two different ion and water balance. The endocrine system’s role in repro-
intracellular signaling pathways. The first signaling pathway duction and development is one of the most obvious mani-
activates an enzyme called adenylate cyclase, which cat- festations of cellular signaling. For example, when female
alyzes the production of cAMP in the recipient cell, causing Hamadryas baboons are ready to mate, a variety of en-
cAMP secretion. The second signaling pathway causes the docrine signals cause the development of a characteristic
recipient cell to release intracellular calcium, which acts on patch of red, swollen skin around their genitals. These
the proteins of the cytoskeleton to induce amoeboid move- swellings act as a visual signal to attract males, helping to
ments. Together, these two intracellular responses cause promote reproduction. Thus, the endocrine system is re-
an amoeboid slime mold cell that encounters environmen- sponsible for inducing a very large and obvious change in the
tal cAMP to move up the cAMP gradient toward the signal- phenotype of these females. In insects, the endocrine sys-
ing individual, and to add to the secreted cAMP in the tem controls the metamorphosis from larva to butterfly.
environment. As more and more cells respond to the sig- Despite their diversity and complexity, however, the mecha-
nal and begin to aggregate into a small area, the cAMP sig- nisms of endocrine signaling in animals share many fea-
nal intensifies, attracting even more amoeboid cells, and tures in common with the signaling systems of unicellular
increasing the size of the aggregation of cells. Eventually, organisms. In this chapter, you will see the critical role of
the group of cells forms a migratory blob termed a pseudo- these cellular communication mechanisms in allowing ani-
plasmodium. The pseudoplasmodium moves through its mals to perform their complex functions.2
environment until it finds a suitable spot, and then differ-

Cell Signaling and Endocrine Regulation

Overview into its environment. The chemical messenger

then travels through the extracellular fluids until it
Everything that an animal does involves commu- reaches the target cell. At the target cell, the chem-
nication among cells. Moving, digesting food, and ical messenger binds to a receptor, changing the
even reading this text all require the coordinated shape of the receptor and activating signal trans-
action of thousands of individual cells engaging in duction pathways that cause a response within
constant communication. Communication between the target cell. Interactions between chemical
cells occurs when a signaling cell sends a signal to messengers, receptors, and signal transduction
a target cell, usually in the form of a chemical mechanisms allow cells to communicate with each
messenger. Figure 1 summarizes the principal other.
types of cell signaling in animals. Adjacent cells Chemical messengers can travel from a signal-
can communicate directly through aqueous pores ing cell to nearby target cells by diffusion in a
in the membrane called gap junctions, but the ma- process called paracrine communication. These
jority of cells have no direct contact with each messengers can even affect the signaling cell, in a
other. Thus, most cell signaling is indirect, and be- process called autocrine communication. But the
gins when one cell releases a chemical messenger rate of diffusion is limited by distance, and thus

Signaling cell Signaling cell Signaling cell


messenger Signaling
Signal cell

Gap system
Chemical Electrical
messenger signal

Chemical Chemical
messenger messenger
Signal Signal (neurotransmitter)
transduction transduction

Response Receptor
Response Response

Target cell Target cell Target cell Target cell

(a) Direct cell signaling (b) Autocrine and (c) Endocrine signaling (d) Neural signaling
paracrine signaling

Figure 1 An overview of cell signaling Cells messengers called hormones travel long distances via the
communicate either directly, via aqueous pores that connect circulatory system. When the hormone reaches the target cell it
adjacent cells, or indirectly when the signaling cell releases binds to a receptor, initiates signal transduction pathways, and
a chemical messenger into the extracellular environment. causes a response. (d) In neural signaling, electrical signals
(a) Direct cell signaling can occur through pores called gap travel across long distances within a single cell. The electrical
junctions.(b) Paracrine signaling occurs when chemical signal then either passes directly to the target cell via gap
messengers diffuse from the signaling cell to nearby target cells junctions, or triggers the release of a chemical messenger
where they bind to receptors and initiate signal transduction called a neurotransmitter. The neurotransmitter carries the
pathways that cause a response. Autocrine signaling is similar signal to the target cell by diffusing across a short distance,
except that the chemical messenger causes a response in the where it binds to receptors on the target cell, initiates signal
signaling cell. (c) Endocrine signaling occurs when chemical transduction pathways, and causes a response.

Cell Signaling and Endocrine Regulation

diffusion is insufficient to carry signals to distant through cell membranes, but do not dissolve well in
target cells. For long-distance cell-to-cell commu- aqueous fluids such as cytoplasm or blood. Hy-
nication, animals use the endocrine system and drophilic chemical messengers are soluble in the
nervous system. In the endocrine system, the cytoplasm and extracellular fluids, but do not pass
chemical messenger travels from the signaling cell through cell membranes. These fundamental
to the target cell carried by the circulatory system. chemical properties pose a problem that cells must
These endocrine messengers are called hormones. solve in order to communicate with each other.
In the nervous system, an electrical signal travels
across a long distance within a single cell (the neu-
ron), and is transferred to the target cell over a very
General Features of Cell Signaling
short distance, often in the form of a chemical mes- Cells can circumvent the problem of moving a hy-
senger called a neurotransmitter. Animals can drophilic chemical messenger through the lipid
even send chemical messengers between individu- environment of the membrane by communicating
als, a system termed exocrine communication. via gap junctions. Gap junctions are specialized
Although these systems appear to be rather dis- protein complexes that create an aqueous pore
tinct, they actually share many features in common between the cytoplasms of two adjacent cells
at the biochemical level. In this chapter, we first ex- (Figure 2). Gap junctions are composed of inter-
amine the biochemical basis of cell signaling, out- locking cylindrical proteins (called connexins in
lining the shared features of different signaling vertebrates, or innexins in invertebrates) assem-
systems. We look at how cells release chemical bled in groups of four or six to form doughnut-like
messengers, how these messengers travel to the pores (hemichannels or connexons) in the cell
target cell, how they bind to receptors, and how membrane. The hemichannels of two adjacent
they exert their effects through signal transduction cells come together to form a hollow tube, con-
pathways. We devote much of this chapter to a dis- necting the two cells via an aqueous bridge. Thus,
cussion of the fundamental properties of receptors chemical messengers can travel from the signaling
and signal transduction mechanisms, not only be-
cause these processes are involved in the regulation
of every physiological system, but also because you
will encounter receptors and signal transduction
Cell A
mechanisms many times throughout your course.
We then step back from the cellular details of com-
munications mechanisms to take a closer look at Cell B

one of the important cellular communication sys-

tems in animals: the endocrine system.

The Biochemical Basis Pore

of Cell Signaling Connexin

(or innexin)
Cells are separated from their environment by a
phospholipid membrane. Thus, any chemical mes- Hemichannel
senger traveling between two cells must first pass Plasma
from the aqueous cytoplasm of the signaling cell, membrane
of cell A
through its lipid membrane, and into the aqueous
extracellular fluid. At the target cell the messenger Plasma
must then signal across the lipid membrane of the of cell B
target cell into its aqueous cytoplasm. Since most Chemical
chemicals are either soluble in aqueous solutions
(hydrophilic) or soluble in lipids (hydrophobic), Figure 2 The structure of gap junctions Gap
junctions are protein complexes that form aqueous pores
sending a chemical messenger from one cell to an- between adjacent cells. Proteins called connexins (in
other presents a substantial challenge. For exam- vertebrates) or innexins (in invertebrates) form the structure
ple, hydrophobic chemical messengers can pass of the gap junction.

Cell Signaling and Endocrine Regulation

cell to the target cell via gap junctions without ever They can be opened and closed to regulate commu-
leaving an aqueous environment. nication of substances between cells. Increased in-
We can demonstrate that two cells are con- tracellular calcium and decreased intracellular pH
nected via gap junctions by injecting a fluorescent both cause gap junctions to close. The number of
dye that cannot cross the cell membrane into one gap junctions connecting two cells can also be reg-
of the cells. If gap junctions connect two cells, dye ulated on a physiological time scale.
that is injected into one cell will diffuse through Direct communication via gap junctions is a
the gap junctions into the adjacent cell (if the dye very efficient way to send signals, but gap junctions
is small enough to pass through the pore), and can only form between adjacent cells. Animals need
both cells will start to fluoresce. If no gap junctions other strategies for sending signals to more distant
are present, the dye will remain in the first cell be- cells, or to neighboring cells that are not connected
cause it is unable to cross the membrane, and the by gap junctions. This kind of signaling is called
second cell will not fluoresce. indirect cell signaling, and involves three steps:
In most physiological situations, direct com-
1. Release of a chemical messenger from the sig-
munication via gap junctions involves the move-
naling cell into the extracellular environment
ment of ions between cells. The movement of ions
into or out of a cell can act as a signal by causing 2. Transport of the chemical messenger through
a change in the membrane potential that triggers a the extracellular environment to the target cell
response in the target cell. This rapid communica- 3. Communication of the signal to the target cell
tion of signals between adjacent cells is a simple via receptor binding
way to coordinate cellular responses. The move-
ment of ions through gap junctions helps to coor-
dinate the contraction of smooth and cardiac
Indirect signaling systems form
muscle, and is involved in the transmission of
a continuum
electrical signals between some nerve cells. Other Although the systems that animals use for indirect
small molecules can also move between cells via signaling are often discussed as if they were quite
gap junctions, including a variety of intracellular different from each other, they are actually just
signaling molecules such as cyclic adenosine specialized ways of achieving the same result. In
monophosphate (cAMP). Thus, gap junctions fact, at the biochemical level they share a great
play a critical role in coordinating physiological deal in common. Table 1 shows some of the simi-
responses at the tissue level. Gap junctions are larities and differences between the various types
not just passive channels between adjacent cells. of cellular communication. In general, autocrine,

Table 1 Comparison of systems for cell-to-cell communication.

Feature Paracrine Nervous Endocrine Exocrine
Secretory cell Various Neural Endocrine Various
Target cell Most cells in body Neuron, muscle, Most cells Sensory and neural
endocrine in body
Signal type Chemical Electrical and Chemical Chemical
Maximum signaling Short Long intracellularly, Long Very long
distance short across synapse
Transport Extracellular fluid Synapse Circulatory External environment
Speed Rapid Rapid Slower Various
Duration of Short Short Longer Various

Cell Signaling and Endocrine Regulation

paracrine, neural, endocrine, and exocrine com- the external environment (e.g., air or water) to ex-
munication systems differ largely in the type of cell ert its effects on a different individual.
involved in messenger secretion and in the way The differences in the mechanisms that the var-
that the messenger is transported to the target cell. ious types of communication systems use to trans-
In contrast, the mechanisms governing the release port chemical messengers from the signaling cell to
of the chemical messenger from the signaling cell, the target cell result in differences in the speed of
the types of chemical messengers utilized, and the communication of these systems. Autocrine and
mechanisms for communicating the signal to the paracrine communication are very rapid, because
target cell are actually very similar among systems. chemical signals need only diffuse across very small
The most important distinction among the dif- distances. Diffusion is a rapid process at these
ferent systems for cellular communication is the scales, so autocrine and paracrine communication
distance across which the chemical messenger occurs on a time scale of milliseconds to seconds.
must travel. In autocrine and paracrine communi- Nervous communication is similarly rapid. Propa-
cation, the chemical messenger simply diffuses gation of electrical signals within a neuron occurs
through the extracellular fluid from the signaling on a millisecond scale, and diffusion of a neuro-
cell to the target cell. Because the rate of diffusion transmitter across the synapse is also rapid. In con-
is limited by distance, autocrine and paracrine sig- trast, endocrine communication is usually slower,
nals are localized, affecting only those target cells because it relies on transport of hormones in the
that are within a short distance of the signaling circulatory system. Depending on the organism,
cell. Intercellular signaling also occurs across short blood may require several seconds to minutes to
distances in the nervous system, at a structure make a complete circuit around the body. In addi-
called the synapse, a region where the signaling tion, endocrine hormones are often longer-lived in
cell and the target cell are very close together. Sig- extracellular fluids than are paracrines or neuro-
nals can move from cell to cell across the synapse transmitters, increasing the length of time over
via gap junctions, if they are present, in a form of which they can have an effect.
direct cell-to-cell communication. Alternatively, Only neurons act as the secretory cells in ner-
neurotransmitters can carry a signal across the vous communication, but a variety of cell types can
synapse by diffusing from the signaling cell to the be involved in exocrine and endocrine communi-
target cell, where they bind to receptors. Because cation. The distinction between nervous and en-
neurotransmitters diffuse from the signaling cell to docrine signaling is, however, somewhat blurry.
the target cell across the synapse, this mechanism Some neurons can secrete neurotransmitters di-
of synaptic communication is similar to paracrine rectly into the circulatory system, in which case
communication. Although cell-to-cell communica- the messenger is termed a neurohormone, be-
tion in the nervous system can only occur across cause it is secreted by a neuron but acts like a hor-
short distances, nervous signals can be communi- mone. The secretory cells of the exocrine and
cated across very long distances. Unlike other endocrine tissues are often grouped into struc-
forms of cellular communication, however, long- tures called glands (Figure 3). Endocrine glands
distance nervous communication occurs within a release their secretions (hormones) directly into
single cell. The unique structure of neurons allows the circulatory system. The endocrine cells within
electrical signals to be propagated across a long these glands are typically very specialized for their
distance within a single cell without degrading. secretory function. However, there are many hor-
The endocrine system can regulate the activities of mones that are not secreted by endocrine glands.
distant cells, tissues, and organs by sending For example, cells within the atria of the heart re-
chemical signals through the blood in the form of lease a hormone called atrial natriuretic peptide
hormones. Because they are carried by the that is involved in the regulation of blood pressure.
circulatory system, rather than moving only by Thus, the distinction between endocrine commu-
diffusion, hormones can quickly travel across nication and other types of intercellular communi-
long distances through the body. In exocrine com- cation can be difficult to elucidate when viewed
munication, a chemical termed a pheromone from the perspective of the signaling cell.
is released by one individual and travels through Exocrine glands release their secretions into
ducts that lead to the surfaces of the body (including

Cell Signaling and Endocrine Regulation

External environment External environment

cells Duct


Circulatory system Circulatory system

(a) Exocrine gland (b) Endocrine gland

Figure 3 The structure of exocrine and endocrine glands Exocrine glands

secrete chemicals into ducts that lead to the surface of the body, whereas endocrine glands
secrete hormones directly into the circulatory system.

the skin, respiratory surfaces, and the surface of the gers use different mechanisms for signaling than do
gut). Exocrine secretions that contain pheromones hydrophilic messengers, because hydrophobic
are involved in animal-to-animal communication, messengers can diffuse freely across cell
but exocrine secretions can also participate in many membranes whereas hydrophilic messengers can-
processes in addition to communication, including not. Table 2 summarizes the similarities and differ-
locomotion, digestion, and prey capture. For exam- ences between hydrophilic and hydrophobic
ple, exocrine mucus secretions form a protective chemical messengers in each step of indirect cell
layer over many epithelia, including the gills of fish signaling.
and the lungs of terrestrial animals. Mucus secre- There are six main classes of chemicals that
tions can also help in locomotion, as in the slime are known to participate in cellular signaling in an-
trails of slugs and snails. Saliva produced in the imals: peptides, steroids, amines, lipids, purines,
mouth of mammals begins digestion, and helps food and gases. All known hormones are peptides,
to slide down the esophagus. Spiders make silk, a steroids, or amines, whereas there are examples of
very specialized exocrine secretion, to trap prey. all six classes of messengers acting as autocrines,
Because all of the different forms of cell signal- paracrines, or neurotransmitters. In the next sec-
ing share so many features in common, in the next tions we look at each of these main classes of
sections we begin our consideration of the bio- chemical messengers to see how their biochemical
chemical basis of cell signaling without separating properties affect their release from the signaling
the different types of signaling used by animals. In cell, transport through the extracellular fluid, and
this way, we can clearly see how cells have solved actions on the target cell.
the general problem of sending chemical signals
across the cell membrane when direct communi-
cation is not possible.
Peptide Messengers
Amino acids, peptides, and proteins can all act as
The structure of the messenger determines signaling molecules. Amino acids typically act as
the type of signaling mechanism neurotransmitters, whereas peptides and proteins
The chemical structure of the messenger is the crit- may be autocrines, paracrines, neurotransmitters,
ical property that affects the way in which indirect neurohormones, hormones, or pheromones. Pep-
signaling is accomplished. Hydrophobic messen- tide and protein messengers consist of two or

Cell Signaling and Endocrine Regulation

Table 2 A comparison of hydrophilic and hydrophobic chemical messengers.

Feature Hydrophilic messengers Hydrophobic messengers

Storage Intracellular vesicles Synthesized on demand
Secretion Exocytosis Diffusion across membrane
Transport Dissolved in extracellular fluids Short distances: dissolved in extracellular fluid
Long distances: bound to carrier proteins
Receptor Transmembrane Intracellular or transmembrane
Effects Rapid Slower or rapid

more amino acids linked in series, and range in in cosmetic medicine to reduce facial wrinkles
size from 2 to 200 amino acids in length. Chains of such as frown lines.
fewer than 50 amino acids are usually called pep- Peptide hormones are often synthesized as large,
tides, while the word protein is used for longer inactive polypeptides called preprohormones
chains. Peptide and protein messengers are hy- (Figure 4). Preprohormones contain not only one or
drophilic chemicals that cannot diffuse across the more copies of a peptide hormone or hormones, but
membranes, but are soluble in aqueous solutions. also a signal sequence that targets the polypeptide
for secretion. The signal sequence is cleaved from the
preprohormone prior to being packaged into secre-
Peptide messengers are released tory vesicles, forming the prohormone, which like
by exocytosis the preprohormone is usually inactive. The secretory
Peptide and protein messengers are synthesized vesicle contains proteolytic enzymes that cut the pro-
on the rough endoplasmic reticulum along with hormone into the active hormone or hormones. The
most of the other proteins destined for secretion signaling cell then releases the active peptide hor-
from the cell. The peptides are then packaged into mone by exocytosis.
vesicles for either immediate release, or storage Figure 5 shows an example of a preprohor-
for later use. Most of the peptide hormones and mone, the one containing arginine vasopressin
neurotransmitters are synthesized in advance and (AVP), also known as antidiuretic hormone (ADH).
stored for later release, whereas paracrine pep- Ribosomes on the exterior of the rough endoplas-
tides such as the cytokines are synthesized only mic reticulum translate the preprovasopressin
on demand. We can see the importance of regu- mRNA into protein. The signal peptide directs the
lated exocytosis of stored messenger by examining newly synthesized polypeptide to the interior of the
the effects of botulinum toxin, a protein produced rough endoplasmic reticulum. The signal peptide is
by the bacterium Clostridium botulinum. This pro- then cleaved off, forming provasopressin, which is
tein blocks the regulated exocytosis of neurotrans- packaged into secretory vesicles. In the secretory
mitters traveling between nerves and muscles, vesicles it is cleaved into three different peptides:
preventing muscle contraction and causing paral- vasopressin, neurophysin, and a glycoprotein. Argi-
ysis. Exposure to a large dose of this toxin causes nine vasopressin is a hormone that acts on the kid-
the disease botulism, which is characterized by ney to regulate the reabsorption of water. The
weakness and paralysis, generally starting in the functions of neurophysin and the glycoprotein are
area of the head and progressing to paralysis of not yet well understood, but they may be involved
the muscles of the rest of the body, including those in the proper sorting and secretion of arginine va-
involved in swallowing and breathing. If un- sopressin.
treated, an individual with a severe case of botu-
lism is likely to die of respiratory failure. Although
the botulinum toxin (also called botox) is one of the
Peptide messengers dissolve
most potent poisons known, it can be used as a
in extracellular fluids
medical therapy. Injecting small amounts of botox Once released from the signaling cell, a chemical
directly into a muscle leads to local paralysis, and messenger must move through the extracellular
can be used to treat muscle spasms. It is also used fluid to the target cell. Hydrophilic chemical

Cell Signaling and Endocrine Regulation

Golgi apparatus


Prohormone Prohormone
Signal hormone


Figure 4 Synthesis of peptide hormones Peptide further processing and sorting. In the Golgi apparatus, the
hormones are synthesized by ribosomes on the rough prohormone is packaged into secretory vesicles, where it is
endoplasmic reticulum, often as large preprohormones. The cleaved into active hormone and one or more peptide fragments.
preprohormone enters the rough endoplasmic reticulum, where The secretory vesicle fuses with the plasma membrane,
the signal sequence is cleaved off. The resulting prohormone is releasing its contents by exocytosis.
packaged into vesicles that move to the Golgi apparatus for

Arginine Glycoprotein
vasopressin messengers such as peptides and proteins dis-
Signal Neurophysin solve well in aqueous solutions and can easily
peptide move from the signaling cell to the target cell, ei-
ther by diffusion or carried by the circulatory
SP AVP NPH GP Preprovasopressin
system. Peptides messengers are usually broken
down and removed from extracellular fluids by
Signal peptide cleaved proteolytic enzymes. The rate of this breakdown
endoplasmic can be measured as the messenger’s half-life—
reticulum the time taken to reduce the concentration of the
messenger by half. Peptide messengers gener-
SP AVP NPH GP Provasopressin ally have half-lives ranging from a few seconds
to a few hours. As a result of these short half-
lives, the signaling cell must continually produce
messenger in order to cause a sustained re-
sponse in a target cell.
Peptides bind to transmembrane
AVP NPH GP Hydrophilic signaling molecules such as peptides
Figure 5 The synthesis of arginine vasopressin and proteins cannot pass through the membrane of
(AVP) AVP is synthesized on the rough endoplasmic reticulum as a the target cell, but instead bind to transmembrane
large polypeptide, preprovasopressin, which contains a signal peptide receptors (Figure 6). The extracellular portion of a
(SP), AVP, neurophysin (NPH), and a glycoprotein (GP). In the rough