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IntracellularIntracellular

CSIM2.23 SIGNALING PATHWAYS

CELL SIGNALLING

1.
2.
3.
4.

Endocrine; hormone secretion into blood by endocrine gland, target distant cells
Autocrine; target sites on same cell (give message to yourself)
Paracrine; target adjacent cell (Baling kertas utk bagi mesej)
Juxtacrine; signalling by plasma membrane-attached proteins. (bagi kertas by hand)

SIGNAL TRANSDUCTION
1. Signal transduction occurs when an extracellular signaling molecule activates a specific
receptor located on the cell surface or inside the cell.
2. In turn, this receptor triggers a biochemical chain of events inside the cell, creating a
response.
3. Depending on the cell, the response alters the cell's metabolism, shape, gene expression, or
ability to divide.
4. The signal can be amplified at any step. Thus, one signaling molecule can cause many
responses

EXTRACELLULAR RECEPTORS
1. Signal transduction occurs as a result of a ligand binding to the outside; the molecule does
not pass through the membrane.
2. Examples of extracellular receptors;

IntracellularIntracellular
LIGAND-GATED ION CHANNELS

Ligand binding causes a drastic change in the permeability of the

channel.
React very quickly to stimulus.
Which open to allow ions such as Na+, K+, Ca2+, or Cl to pass
through the membrane in response to the binding of a ligand, such
as a neurotransmitter.
The function of such receptors located at synapses is to convert the
chemical signal of pre-synaptically released neurotransmitter
directly and very quickly into a postsynaptic electrical signal.
An example of this mechanism is found in the receiving cell of a
neural synapse. The influx of ions that occurs in response to the
opening of these channels induces action potentials, such as those
that travel along nerves, by depolarizing the membrane of postsynaptic cells, resulting in the opening of voltage-gated ion
channels.
An example of an ion allowed into the cell during a ligand-gated ion channel opening is
Ca2+; it acts as a second messenger initiating signal transduction cascades and altering
the physiology of the responding cell.
Ach, GABA, 5-HT3, glutamate, glycine, prinergic (P2X). Mineralocorticoid HPT.

G-PROTEIN COUPLED RECEPTOR (GPCR)/7-TM RECEPTORS

Contain seven transmembrane helices and are linked to a heterotrimeric (have three
different subunit) G protein.
Example of receptors; adrenergic receptors and chemokine receptors
Signalling pathways:
i.
Ligand binds to GPCR
ii.
GPCR undergoes conformational change
iii.
subunit exchanges GDP fro GTP
iv.
subunit dissociates and regulates target
proteins
v.
Target proteins relay signal via 2nd messenger
vi.
GTP hydrolyse to GDP
Regulates
Sense of visual, gustatory, smell,
behavioural and mood regulation (serotonin,
dopamine)
immune system activity and inflammation,
autonomic nervous system transmission,
homeostasis modulation (water balance) and
Growth and metastasis some types of tumour.

TYROSINE KINASE-LINKED

One of enzyme linked receptors.

Receptor tyrosine kinases (RTK) are transmembrane proteins with an intracellular kinase
domain and an extracellular domain that binds ligands; growth factor receptors such as
insulin receptors.
When ligand bind, they cause neighbouring RTKs to associate and formed cross-liked
dimers in the plasma membrane; the dimer is stabilized by ligands binding to the
receptor. They need to act in pairs because cross-linking activates the tyrosine kinase
activity in these RTKs through phosphorylation. Activating the tyrosine and they start
getting phosphorus.

IntracellularIntracellular

Regulate cell growth, differentiation and survival.

Kinase: has the ability to transfer phosphorus molecules. Usually from a high energy
substance like ATP to intracellular proteins
which activates them.
Once the tyrosine is phosphorylated, they
serve as docking platforms. Different proteins
can come by and attach themselves.
Allow activation of multiple different
intracellular signaling pathway at the same
time. A single stimulus can trigger multiple
paths
RTKs primarily regulates cell growth. Many
cancers involve mutations of RTKs.
Target for Herceptin (breast cancer drugs).

INTRACELLULAR
1. Intracellular receptors are soluble proteins localised within their
respective areas. The typical ligands for nuclear receptors are
lipophilic hormones like the steroid, testosterone and
progesterone and derivatives of vitamin A and
2. D.
3. To initiate signal transduction, the ligand must pass through the
plasma membrane by passive diffusion. On binding with the
receptor, the ligands pass through the nuclear membrane in to
the nucleus, enabling gene transcription and protein production.
NUCLEAR RECEPTOR SUPER-FAMILY

ligand-sensitive transcription factors; steroid & thyroid hormones

DISEASE ASSOCIATED TO CELL SIGNALLING

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NEPHROGENIC DIABETES INSIPIDUS - X-LINKED NDI
1. Improper response of the kidney to anti-diuretic hormone (ADH)/Arginine Vasopressin (AVP),
leading to a decrease in the ability of the
kidney to concentrate the urine by
removing free water.
2. UNLIKE central/neurogenic diabetes insipidus
which is caused by insufficient levels of
ADH/AVP
3. When the function of AVPR2 is lost, the
disease Nephrogenic Diabetes Insipidus
(NDI) results. AVPR2 is a protein acts as
receptor for arginine vasopressin and
belongs to subfamily of G-protein-coupled
receptors.
4. Causes polyuria but no elevated glucose concentration as opposed to DM.
5. SS: excessive thirst, polyuria, dehydration. As pituitary function is normal, ADH levels are
likely to be a normal or raised. Increased plasma osmolarity (deficient fluid volume). LOW
potassium level. HIGH calcium levels.
6. X-linked genetic defect. Defect in AVPR2. LOW BP, tachycardia, shock, signs of dehydration.
7. Management: drink enough fluid, treat underlying cause, low salt and low protein diet.
8. Tx: hydrochlorthiazide (allow increased excretion of Na+ and water, thereby reducing the
serum osmolarity and eliminating volume excess) and amiloride. GAIN of signal function
Siadh
9. Sequencing the AVPR2 gene

SYNDROME OF INAPPROPRIATE ANTI-DIURETIC HORMONE SECRETION

(SIADH)
1. Excessive release of ADH from the posterior pituitary gland or another source. ADH is to
control the amount of water reabsorbed by kidney nephrons. Preventing water loss in the
kidneys. Acssots on distal convoluted tubule as well as on the collecting duct and causes
water retention.
2. Hence ADH effectively dilutes the blood. When the blood is diluted enough, it will be
detected by the hypothalamus and switch off the release of ADH. Decreasing [ADH] inhibits
aquaporins. Hence less water reabsorbed.
3. In SIADH, ADH IS NOT INHIBITED due to V2R mutations. Hence there is excessive release of
ADH (increase water retention within the body).
4. Often leads to HYPONATRAEMIA; plasma sodium levels are lowered and total body fluid is
increased.
5. Causes: Meningitis, head injury (SAH), cancers (lung), infections, Guillain-Barre syndrome,
drugs, hypothyroidism, sarcoidosis.
6. Treatment: fluid intake restriction, various medicines and management of underlying cause.

LIDDLE SYNDROME AUTOSOMAL DOMINANT

1. Pseudo-aldosteronism, is a genetic disorder inherited in an autosomal dominant manner.
2. Presented with early onset HPT associated with low plasma renin activity, metabolic
alkalosis, low blood potassium, and normal/low aldosterone.
3. Dysregulation of an ENaC. The mutation changes a domain in ENaC so it is no longer
degraded correctly by the ubiquitin proteasome system. No negative feedback
4. Involving increased activity of the epithelial Na channel (ENaC) which causes the
kidneys to excrete K but retain too much Na and water, leading to hypertension.
5. Therefore, there is increased activity of this channel leading to increased sodium
reabsorption. The increased sodium reabsorption leads to hypertension due to an increase in
extracellular volume
6. Treated with a combination of low sodium diet and potassium-sparing (amiloride,
spironolactone) diuretic drugs
7. Ix: urinary electrolytes.
8. Presentation
a. Low blood potassium; weakness, fatigue, palpitations, or muscular w/ness.
9. Difference with hyperaldosteronism (Conns Syndrome); ALDOSTERONE in CS is HIGH, but in
Liddle, it is LOW to NORMAL.
VON HIPPEL LINDAU AUTOSOMAL DOMINANT
1. It is disease result from a mutation in the von Hippel-Lindau tumour suppressor gene. VHL is
needed to inhibit hypoxia inducible factor (HIF).
2. HIF is necessary for tumor growth because most cancers demand high metabolic activity and
are only supplied by structurally or functionally inadequate vasculature.
3. It is autosomal dominant familial cancer syndrome.
4. Loss of VHL function, hypoxia-independent up-regulation of HIF
5. SS: headaches, problems with balance and walking, dizziness, weakness of the limbs, vision
problems, and high blood pressure
6. Condition associated with VHL; angiomatosis, hemangioblastomas, pheochromocytoma,
renal cell carcinoma, pancreatic cysts (pancreatic serous cystadenoma), endolymphatic sac
tumor, and bilateral papillary cystadenomas of the epididymis (men) or broad ligament of
the uterus (women).
7. Usually affect the retina. Loss of vision is common.