M&R Receptor effector mechanisms

Question 1

What are the 3 types of cell surface receptor?

Answer 1

1. Ligand-gated ion channels e.g. nAChR
2. Receptors with intrinsic enzymatic activity (protein kinases) e.g. insulin receptor. Enzyme phosphorylates the enzyme itself & other substrates
3. G protein coupled receptors e.g. mAChR

Question 2

How do GPCRs respond to stimuli and cause a change in cellular activity?

Answer 2

An activated GPCR reacts with a G-protein (3 subunits - a, B, gamma)
The GPCR- G protein interaction activates the G protein by causing GTP to exchange for GDP on the alpha subunit (GTPase)

The alpha + beta,gamma complex dissociates into alpha GTP and free beta gamma subunits

Each subunit can then interact with effector proteins e.g. second message-generating enzymes or ion channels

Question 3

What is the general structure of a GPCR?

Answer 3

Single polypeptide chain
7 transmembrane domains
Extracellular N terminal
Intracellular C terminal

Question 4

How is a G-protein signal terminated?

Answer 4

The alpha-GTP and beta-gamma interactions with effectors last until the alpha subunit GTPase hydrolyses GTP back to GDP.
Alpha-GPD and better-gamma subunits then reform

Question 5

Give some broad examples of effectors

Answer 5

• enzymes e.g. adenylyl cyclase ATP –> cAMP, phospholipase C
• ion channels e.g. voltage operated Ca2+ channels

Question 6

How is adenylyl cyclase regulated?

Answer 6

Adenylyl cyclase can be regulated by agonist-stimulation such as

• B-adrenoreceptors
• a2-adrenoreceptors

Question 7

How does adenylyl cyclase exert its actions?

Answer 7

Through cAMP dependent protein kinase (PKA)
cAMP binds to the regulatory subunits of PKA which activates the catalytic subunits
The catalytic subunits then phosphorylate target proteins in the cell

Question 8

Describe the role of phospholipase C

Answer 8

Phospholipase C catalyses the cleavage of membrane phospholipid PIP2 into two secondary messengers: IP3 and DAG.
(PIP2 – phospholipase C —> IP3 + DAG)

IP3 binds to the IP3 receptor on the ER
This releases CA2+

Calcium then binds to phosphokinase C, which binds to DAG

Question 9

How is phospholipase C regulated?

Answer 9

Phospholipase C can be regulated by agonist stimulation
eg
- a1-adrenoreceptors
- M1 muscarinic receptors

Question 10

Give examples of signalling pathways in the body

Answer 10

1. Inotropy in the heart
   Adrenaline and NA interact with B1-adrenoreceptors to increase force of contraction by increasing the opening of VOCCs.
2. Smooth muscle contraction
   NA interacts with a1-adrenoreceptors to cause vasoconstriction (IP3 releases Ca2+)
   ACh can interact with bronchiole M3-muscarinic receptors to cause bronchoconstriction

(all utilise the GCPR - phosoplipase C - IP3 / DAG - phosphokinase C pathway)

3. Neurotransmitter release
   In CNS and PNS neurotransmitter release is modulated by presynaptic GPCRs. The beta-gamma subunit inhibits voltage operated Ca2+ channels reducing Ca2+ influx.