Physiology

Unit 1

CELL SIGNALING: CHEMICAL MESSENGERS
AND SIGNAL TRANSDUCTION PATHWAYS

 Cell Communica4on
Homeosta4c mechanisms maintain a normal balance
of the bodys internal environment
Opera4on of control systems require cells to be able to
communicate with each other
Intercellular communica4on is mostly by chemical
messengers
Ligands
NeurotransmiCers Paracrine Agents
Rapid Released by cell
Short distance Binds to neighboring cells
Hormones Autocrine agents
Slower Released by cell
Longer distance Binds to self cell
Gases
Receptors
Cell must have a
mechanism to detect a
chemical messenger
Receptor protein has a
binding site for the
chemical messenger
Signal transduc.on
pathways converts
chemical signals to a
biologically meaningful
response
 Characteris4cs of Receptors
Specicity
Single messenger
Mul4ple messengers
Anity
Satura4on
Compe44on
Antagonists
Agonists

Compe44on
Messengers or molecules
with a similar structure
compete for binding sites
on receptors
Antagonists
Blocks the endogenous
messenger and prevents the
response
Agonists
Binds to receptor and
triggers the cells response
Mimics endogenous
messenger
 Regula4on of Receptors
Receptors are subject to physiological regula4on
Number of receptors
Anity of receptors
Down-regula4on
Persistent, high [chemical messenger]
Desensi4zing
Local nega4ve feedback
Up-regula4on
Prolonged, low [chemical messenger]
Supersensi4vity
 Signal Transduc4on Pathways
Sequence of events from binding of a chemical
messenger and the cells response
Receptor ac4va4on is the ini4al step
Messenger-receptor binding causes a conforma4on
change in the receptor
Response may change (alter ac4vity/transla4on of cell
proteins)
Permeability
Transport proper4es
Voltage change in the membrane
Cell metabolism
Cell secretory ac4vity
Cells contrac4le ac4vity
Lipid Soluble Messengers
Messengers bind to
intracellular receptors
Lipid soluble
Messengers are inac4ve
un4l bound to a
receptor
Ac4vated receptor acts
as a transcrip.on factor
Cor4sol
Steroid hormones
Thyroid hormones
 Water Soluble Messengers
Binds to receptor on the extracellular surface of the
plasma membrane
Water soluble messengers
Pep4de hormones
NeurotransmiCers
Paracrine/autocrine compounds
Common mechanisms of receptors
1. Ligand-gated ion channels
2. Receptors func4on as enzymes (tyrosine kinases)
3. Bind to and ac4vate cytoplasmic JAK kinases
4. G-protein coupled receptors that ac4vate G-proteins
which then act on ion channels or enzymes in the plasma
membrane
 Water Soluble Messengers
Pathway Components
Pathway Components
1. Receptor Ac4va4on
Water soluble chemical messenger binds to a plasma membrane
receptor
2. Receptor ac4va4on generates a second chemical
messenger in the cytoplasm
3. Signal transduc4on: a series of chemical reac4ons that
result in the cells response
Protein kinase
Any enzyme that phosphorylates other enzymes or
proteins by transferring a phosphate group from ATP
Ac4vates the enzyme or protein
Changes the conforma4on of the phosphorylated protein
Ligand Gated Ion Channels
Receptor ac4va4on
opens an ion channel
Increases membrane
permeability of that ion
Ion diuses across the
plasma membrane
Changes membrane
poten4al
Receptors That Func4on as Enzymes
Intrinsic enzyme ac4vity
Receptor tyrosine kinases
Inuence
cell prolifera4on
Cell dieren4a4on
apoptosis
Receptor ac4va4on includes
ac4va4on of the enzyme
por4on
The receptor phosphorylates its
own tyrosine groups
Phosphotyrosines serve as
docking sites for cytoplasmic
proteins that ac4vate signaling
pathways inside the cell
Ac4vate cytoplasmic proteins by
phosphoryla4on
Receptors That Ac4vate JAK Kinases
Receptor ac4va4on
ac4vates the associated
JAK kinase
JAK kinases
phosphorylate
transcrip4on factors
Cytokines ac4vate JAK
kinase receptors
Proteins secreted by cells
of the immune system
G-Protein-Coupled Receptors
Very common
G-protein complex bound
to a receptor
Receptor ac4va4on
results in dissocia4on of
the sub-unit
-sub-unit ac4vates an
ion channel or an
enzyme in the plasma
membrane

 Cyclic AMP (cAMP)
2nd messenger
Source
1st messenger ac4vates a G-protein coupled receptor
G-protein ac4vates adenylyl cyclase
Adenylyl cyclase catalyzes the conversion of ATP to cAMP
Ac4on:
cAMP ac4vates cAMP-dependent protein kinase A
Protein kinase A ac4vates a large number of dierent proteins
Ini4ates an amplica4on cascade
cAMP may also de-ac4vate enzymes
Rate limi4ng step in glycogen synthesis
 Cyclic AMP (cAMP)
2nd messenger

Phosphodiesterase deac4vates cAMP to AMP

Signal Amplica4on by cAMP
 Diacylgylerol (DAG)
2nd messenger

Source
1st messenger ac4vates a G-protein coupled receptor
G-protein ac4vates Phospholipase C
Phospholipase C splits a plasma membrane phospholipid to
diacylglycerol (DAG)
Ac4on
Ac4vates protein kinase C
Protein kinase C ac4vates other intracellular proteins

 Inositol Triphosphate (IP3)
2nd messenger
Source
1st messenger ac4vates a G-protein coupled receptor
G-protein ac4vates Phospholipase C
Phospholipase C splits a plasma membrane phospholipid to
inositol triphosphate (IP3)
Ac4on
- IP3 Binds to ligand gated Ca2+ channels on the smooth ER
- Ligand-gated Ca2+ channels open and increase cytoplasmic
[Ca2+]
- Increased calcium levels con4nue the cascade of events
leading to the cells response
DAG and IP3
2nd messengers

Protein Kinase C is
ac4vated by DAG and
Ca2+
DAG and IP3
2nd messengers
 Calcium (Ca2+)
2nd messenger
Source
- In the plasma membrane:
- Ligand gated Ca2+ channels
- Voltage gated Ca2+ channels
- G-protein ac4ves Ca2+ channels
- Ca2+ released from the smooth ER (mediated by IP3 or Ca2+
entering the cytoplasm)
- Ac4ve transport of Ca2+ is inhibited by a 2nd messenger
Ac4on
- Ca2+ ac4vates calmodulin
- Ac4vates calmodulin-dependent protein kinases
- Ca2+ binds to and alters protein ac4vity directly
 Calcium (Ca2+)
2nd messenger

Rememberac=ve
transport systems in the
plasma membrane and
organelles maintain
low cytoplasmic [Ca2+]
Maintains an
electrochemical
gradient
 Arachidonic Acid
2nd messenger
Source
1st messenger binds to a g-coupled membrane receptor
which ac4vates an enzyme (Phospholipase 2) present in the
membrane of the cell
An enzyme (Phospholipase 2) splits o arachidonic acid from a
membrane phospholipid
Ac4on
Can be metabolized by two dierent pathways to produce
eicosanoids
Cyclooxygenase (COX) pathway or lipoxygenase (LOX) pathway
Eicosanoids may act as 2nd messengers or as local paracrine/
autocrine agents
Arachidonic Acid
2nd messenger
NSAIDS block the COX pathway
reduce pain, fever,
inamma4on
Adrenal steroids inhibit
phospholipase A2
blocks the produc4on of all
eicosanoids
Eicosanoids are produced
from arachidonic acid
Prostaglandins
Thromboxanes
Leukotrines
 Eicosanoids
Prostaglandins, Thromboxanes, Leukotrines

Signaling molecules in CNS
Hormones
Paracrine/paracrine agents
Some4mes called super hormones
Derived from Omega-3 and Omega-6 faCy acids
Involved in inamma4on and immunity
Very complex control systems

vCor.sol inhibits eicosanoid produc.on

 Stopping Signal Transduc4on
Pathways
Chronic overs4mula4on in cells can be
detrimental
Presence of 2nd messengers are transient
Physiological controls to stop receptor ac4va4on
1. Enzymes in the vicinity metabolize the 1st messenger
2. Phosphoryla4ng the receptor
May decrease its anity for the messenger
May prevent further binding of G-proteins binding to the
receptor
3. Endocytosis of messenger-receptor complex