GPCR

Question 1

Gs coupled

Answer 1

[stimulatory]

activation of adenylyl cyclase to phosphorylate cAMP -> PKA

Question 2

Gq coupled

Answer 2

[stimulatory]

activation of phospholipase C (PLC) to convert PIP2 -> IP3 = Ca2+ release (+ DAG -> PKC)

Question 3

Gi/o coupled

Answer 3

inhibition of adenylyl cyclase
+ opening of K+ channels
+ closing of Ca2+ channels

Question 4

what does desensitisation/tolerance do to conc-response curve?

Answer 4

shift right

Question 5

arrestin

Answer 5

protein that binds to GPCR once activated by ligand to regulate cell signaling

leads to receptor desensitisation + internalisation

Question 6

GPCR-kinase (GRK)

Answer 6

phosphorylate agonist bound receptor, when G protein isn’t bound

serine/threonine kinase

enhances affinity of arrestin to bind to receptor

Question 7

why is homeostasis of cell signaling important?

Answer 7

protects cells from excessive activation (= lethal)

Question 8

allosteric modulation

Answer 8

no agonist function - enhances/inhibits agonist-induced signaling

makes it easier to target sub-types of receptor

Question 9

which binding site do modulators bind to?

Answer 9

allosteric binding site

Question 10

partial agonist

Answer 10

no receptor reserves

Question 11

do more or less efficacious agonist cause less desensitisation?

Answer 11

LESS

MoA less likely to occur - less likely to be activated

Question 12

high efficiency agonists

Answer 12

[e.g. DAMGO]

via mu receptor + Gi/o protein (arrestin)

binds + forces conformation change

Question 13

low efficiency agonists / partial agonists

Answer 13

[e.g. morphine]

via PKC pathway

not as good at forcing conformational change and stabilising it

Question 14

inverse agonists

Answer 14

opposite reaction by stabilising inactive state of receptor

Question 15

> 1 active conformation

Answer 15

2 different agonists can cause desensitisation by different mechanisms

AFFECTS:
1. how agonists cause desensitisation
2. arrestin-binding signaling
3. G protein activated by agonist (can switch between Gs and Gi/o)

Question 16

clathrin

Answer 16

forms chain + pinches membrane to form clathrin-coated pit/vesicle

Question 17

2 pathways from early endosome

Answer 17

1. becomes lysosome -> degraded in cytoplasm
2. becomes late endosome -> recycled to cell membrane

Question 18

pH inside endosome?

Answer 18

low

Question 19

which mechanism causes longer desensitisation?

Answer 19

via PKC (partial agonists e.g. morphine)

not type of receptor that is recycled

Question 20

down-regulation

Answer 20

conc. and affinity of receptors decrease

Question 21

inverse agonists as asthma treatment

Answer 21

[target b2 receptors]

can’t constantly be taken due to tolerance build up

use inverse agonist to stabilise receptor in inactive state (receptor not being activated - no tolerance build up)

no. of receptors on cell surface increases to compensate for low activity

Question 22

problem with using inverse agonists as treatment for asthma

Answer 22

guarantee no asthma attack for 1st month of using inverse agonist while number of receptors are in process of increasing

inverse agonist would make asthma worse if attack happened

Question 23

heterologous desensitisation

Answer 23

signal elsewhere can activate pathway that leads to desensitisation

Question 24

oligermerisation

Answer 24

2 or more receptors which are physically linked

either heterodimers or homodimers

Question 25

GABA-B receptors

Answer 25

only signal as heterodimers

R1 can’t couple to G protein and R2 can’t bind to ligand

= transactivation

Question 26

functional consequences of heterodimerisation

Answer 26

1. altered signaling
2. altered pharmacology (change in affinity and efficacy)
3. altered desensitisation / internalisation