GPCRs

Question 1

What is a GPCR?

Answer 1

G-coupled protein receptor

Question 2

What is a 7TM receptor?

Answer 2

7 Transmembrane receptor, it crosses the membrane 7 times

Question 3

What binds to a 7TM receptor and where?

Answer 3

ligand, outside the cell

Question 4

What activates the G protein?

Answer 4

Binding of a ligand

Question 5

Where are the G proteins found on 7TM receptors?

Answer 5

On the inside of the membrane

Question 6

What are 7TM receptors involved in?

Answer 6

neuronal signalling, vision, smell, taste

Question 7

What receptors are the key target for drugs? And what percentage?

Answer 7

7TM receptors, approximately >30% of drugs target GPCRs

Question 8

What are the effects of different 7TM receptors based on?

Answer 8

By which G-proteins alpha subunit they activate

Question 9

Outline the key points in GPCR signalling

Answer 9

1. Ligand binds to 7TMR
2. 7TMR changes conformation resulting in activation of G protein
3. G protein dissociates from 7TMR, G-alpha-GTP and G-beta-gamma are the active forms formed.
4. G-alpha-GTP binds to effector proteins.
5. G-beta-gamma activates ion channels along membrane.
6. GTP is hydrolysed to GDP, G-alpha is no longer active and rebinds to G-beta-gamma

Question 10

What happens in the activation of the G protein

Answer 10

GDP dissociates from G-alpha and GTP binds. G-alpha-GTP splits from G-beta-gamma

Question 11

What happens after effectors are activated by G-subunits

Answer 11

They go on to activate other proteins which leads to signal cascades and amplification

Question 12

Which has a faster response: ligand-gated ion channels or GPCRs

Answer 12

Ligand-gated ion channels

Question 13

Why are GPCRs slower than ligand-gated channels?

Answer 13

The proteins have to move around in the cell to activate the effectors

Question 14

Why can you get inverse agonists for GPCRs but not ligand-gated channels?

Answer 14

GPCRs appear to have some activity even without a ligand present, therefore inverse agonists are able to reduce this activity without being ‘negative’

Question 15

What is basal activity?

Answer 15

Biological response without a ligand being bound to a GPCR

Question 16

What are 2 factors of drugs that are being improved upon?

Answer 16

Increasing selective targeting, reduce off-target effects

Question 17

What are the 3 GPCR second messenger pathways?

Answer 17

Gs, Gi and Gq

Question 18

What does the effect of adrenergic receptors depend on?

Answer 18

The g-protein that it is coupled to and the identity of the tissue that the receptor is found in

Question 19

Outline the Gq signalling pathway

Answer 19

Receptor and g-protein is activated. This activates Phospholipase C (PIP2 is converted to IP3 and DAG). The increase in IP3 increases concentration of Ca2+ ions = smooth muscle contraction

Question 20

Outline the Gi intracellular signalling pathway

Answer 20

Receptor and g-protein is activated. The enzyme adenylyl cyclase is inhibited (ATP no longer forms cAMP) = less smooth muscle contraction. Production of Ca2+ is inhibited = inhibition of transmitter release

Question 21

Outline the Gs intracellular signalling pathway

Answer 21

Receptor and g-protein is activated. the enzyme adenylyl cyclase is activated (ATP forms cAMP) = heart muscle contraction, smooth muscle contraction) and glycogenosis

Question 22

Which receptors follow the Gi pathway?

Answer 22

Alpha-2

Muscurinic 2 and 4

Question 23

Which receptors follow the Gq pathway?

Answer 23

Muscurinic 1 and 3

Alpha-1

Question 24

Which receptors follow the Gs pathway?

Answer 24

Beta-1

Beta-2

Question 25

What does the production of cAMP do in cardiac myocytes?

Answer 25

Activates protein kinase: Increase in Ca2+, increase myosin ATPase activity, Ca2+ re-uptake into sarcoplasmic reticulum

Question 26

What does the production of cAMP do in smooth muscle and in cardiac muscle?

Answer 26

Smooth muscle: makes myosin relax

Cardiac muscle: activates myosin and increases calcium concentration

Question 27

What does inhibiting the production of cAMP do in smooth muscle and cardiac muscle?

Answer 27

Smooth muscle: myosin is activated

Cardiac muscle: myosin is relaxed

Question 28

Why can GPCRs cause amplification of a signal but ion channels cannot?

Answer 28

GPCRs activate enzymes which can result in more enzymes being activated. Ion channels only let in/ let out ions.

Question 29

What is RTKs?

Answer 29

Receptor Tyrosine Kinases, single transmembrane proteins.

Question 30

What happens to TKRs when a ligand binds?

Answer 30

They dimerise and activate intracellular kinases (transfer of phosphate group)

Question 31

Name 2 examples of what the activation of RTKs can result in

Answer 31

Gene expression, differentiation of cells

Question 32

What are TKRs important for?

Answer 32

Neuronal development and survival

Question 33

Name the main condition that RTKs are targeted by drugs for and a condition that is currently being researched for

Answer 33

Main: cancer
Research: Alzheimer’s

Question 34

Outline the steps for RTK activation

Answer 34

1. 2 signal molecules binds to receptor.
2. Dimer is formed and tyrosine-kinase is partially activated
3. Dimer becomes phosphorylated and is fully activated
4. Inactive relay proteins bind and become activated
5. 2 Cellular responses occur which can result in a cascade of events

Question 35

After RTK is activated what must happen in order for a cascade of events to occur?

Answer 35

Phosphorylation of the protein kinase each time to reactivate it