GPCRs

Question 1

what are the three components of GPCRs

Answer 1

• receptor
• G-protein
• second messanger

Question 2

G-protein structure

Answer 2

• membrane-tethered heteritrimer
• alpha, beta, gamma

Question 3

why must effectors be close to G-proteins

Answer 3

• to efficiently generate second messangers

Question 4

what proportion of drugs target GPCRs

Answer 4

~50%

Question 5

how many transmembrane helices do GPCRs have

Answer 5

• 7 alpha helices

Question 6

where are GPCR termini located

Answer 6

• N-terminus EC
• C-terminus IC

Question 7

what happens to GPCR receptor component upon ligand binidng

Answer 7

• cytoplasmic pocket opens

Question 8

what structural change enables G-portein binding

Answer 8

• TM6 movement outward
• creates a cytoplasmic cleft

Question 9

what are the two classes of G-proteins

Answer 9

• large heterotrimeric
• small monomeric (Ras superfamily)

Question 10

subunits of heterotrimeric G-proteins

Answer 10

• alpha
• beta
• gamma

Question 11

whihc subunit binds GDP/ GTP

Answer 11

• alpha subunit

Question 12

what domains are in the alpha subunit of heterotrimeric G-protein

Answer 12

• Ras domain (GTPase activity)
• alpha helical (AH) domain (GDP clamp)

Question 13

what modification helps membrane attachment in heterotrimeric G-proteins

Answer 13

• lipid modification of alpha and gamma

Question 14

what triggers GDP release form G-alpha

Answer 14

• interaction with activated GPCR

Question 15

what happens after GTP binds to G protein

Answer 15

• G-alpha dissociates from beta-gamma

Question 16

what is the result of G-alpha and beta:gamma dissociation

Answer 16

• both G-alpha and beta:gamma activate effectors

Question 17

why are GPCR signals highly amplified

Answer 17

• one ligand activates many downstream molecules

Question 18

what does Gαs stimulate

Answer 18

• adenylate cyclase -> cAMP production

Question 19

what cascade follows cAMP production in Gαs

Answer 19

cAMP → PKA → phosphorylase kinase → glycogen phosphorylase

Question 20

final outcome of Gαs (Glucagon Pathway)

Answer 20

• glycogen -> glucose-6-phosphate

Question 21

Gαs (Glucagon Pathway) Level of amplification

Answer 21

• 1 glucagon → ~10⁸ glucose molecules

Question 22

speed of Gαs (Glucagon Pathway) response

Answer 22

• <10seconds

Question 23

what GPCR is involved in vision

Answer 23

• rhodopsin

Question 24

what activates rhodopsin

Answer 24

• light
• via retinal isomerisation

Question 25

What does Gαt activate for vision?

Answer 25

- cGMP phosphodiesterase

Question 26

what happens to ion channels when Gαt activates

Answer 26

- close -> cell hyperpolarises

Question 27

Gαt activation signal amplification scale

Answer 27

- Prevents 10⁶–10⁷ Na⁺ ions entering

Question 28

receptor desentisisation

Answer 28

- cells reduce their responsiveness to stimulus due to repeated or chronic exposure to agonists

Question 29

what enzyme phosphorylates GPCRs

Answer 29

- GRK (G-protein receptor kinase)

Question 30

what binds GPCRs after phosphorylation

Answer 30

- arrestin

Question 31

effects of arrestin binding GPCRs

Answer 31

- blocks G-protein binding - promotes receptor internalisation

Question 32

How is Gα activity turned off?

Answer 32

- GTP -> GDP via intrinsic GTPase activity

Question 33

what enhances Gα activity turning off

Answer 33

- RGS protein (GAPs)

Question 34

what happens to internal brakes if ligand still present

Answer 34

- tuns off but G-protein reactivates

Question 35

how is cAMP degraded

Answer 35

- by phosphodiesterases -> AMP

Question 36

What limits sensitivity?

Answer 36

- Negative feedback - Receptor desensitisation - GTPase activity - Second messenger breakdown