Signal Transduction

Question 0

Give some examples of G-protein coupled receptor mutations.

Answer 0

• abnormal photoreceptors -> retinitis pigmentosa (loss of function)
• abnormal V2 vasopressin receptor -> nephrogenic diabetes insipidus (loss of function)
• constitutively active lutenising hormone receptor -> familial male precocious puberty (gain of function)

Question 1

How can signals be traduced across membranes?

Answer 1

• ligand-gated ion channels e.g. nACHR
• receptors with intrinsic enzymatic activity e.g. Tyrosine kinase
• G-protein coupled receptors e.g. mACHR

Question 2

Outline the structure of GPCRs.

Answer 2

• single polypeptide chain
• 7TM (ligand-binding domain)
• extracellular N terminal (ligand-binding domain)
• intracellular C terminal

Question 3

How does cholera toxin affect G-proteins?

Answer 3

Eliminates GTPase activity of Gs

Gs becomes irreversibly activated.

H2O channels open in intestinal lumen

Increased loss of watery faeces

Question 4

How does pertussis toxin affect G-proteins?

Answer 4

Interferes with GTP exchange of Gi

Gi becomes irreversibly inactivated

No inhibition of adenylyl cyclase, therefore c.AMP increases

Release of insulin -> hypoglycaemia

Question 5

Outline the sequence of events in agonist-stimulated regulation of adenylyl cyclase.

Answer 5

G protein is stimulatory (s) or inhibitory (a)

GTP exchanged for GDP on alpha subunit

Activated alpha subunit activates adenylyl cyclase

ATP -> c.AMP

c.AMP activates protein kinase A by binding to the regulatory subunit of PKA which activates the catalytic subunits

Question 6

Outline the sequence of events of agonist-stimulated regulation of phospholipase C.

Answer 6

G-protein (q)

GTP exchanged for GDP on alpha subunit

Activated alpha subunit activated phospholipase C on the membrane

PIP2 is cleaved into diacylglycerol (DAG) and IP3

IP3 binds to receptors on the SR to release calcium which activated protein kinase C along with DAG

Question 7

Outline the signalling pathway which causes inotropy in the heart.

Answer 7

Adrenaline & noradrenaline -> ventricular beta-1-adrenoceptors

• > increased c.AMP -> PKA activated -> VOCC activated
• > influx of calcium -> increased contractility -> increased force of contraction

Question 8

Outline the signalling pathways involved in smooth muscle contraction.

Answer 8

SYMPATHETIC:
Noradrenaline & adrenaline -> alpha-1-adrenoceptors on vascular smooth muscle -> Gq activated -> vasoconstriction

PARASYMPATHETIC:
Acetylcholine -> M3-muscarinic receptors on bronchiolar smooth muscle -> Gq activated -> bronchoconstriction

Question 9

Outline the signalling pathway involved in modulation of neurotransmitter release.

Answer 9

Morphine -> u-opioid receptor -> Gi -> inhibits VOCCs -> decreased calcium influx -> reduced neurotransmitter release