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Cell and molecular extras > Lecture 9 GPCR 1 > Flashcards

Lecture 9 GPCR 1 Flashcards

1
Q

GPCRs are the largest family of…

A

membrane anchored receptors in the genome

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2
Q

Each receptor in the family shares…

A

1/more structurally homologous domains = ligand binding domains or signal transduction domains

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3
Q

What domain is conserved

A

signal transduction domains

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4
Q

What distinguishes GPCR classes

A

EC domain defining ligand BS

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5
Q

How many TM domains

A

7 (alpha helices)

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6
Q

Which domain is crucial for the transduction of a ligand binding

A

TM3 central next to binding pocket that may be buried

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7
Q

What else contributes to ligand binding

A

Other TM domains or EC N terminus

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8
Q

Describe dynamic equilibrium

A

Eq of active and resting state

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9
Q

Describe resting state

A

R pinched in

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10
Q

Describe activated state

A

Agonists binds
stabilises active conformation
TM3 detects
Conf change and e released to TM5/6 to move to reveal G protein binding pocket so R can signal

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11
Q

C terminus of GPCR

A

For reg e.g. phos/protein-protein

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12
Q

For every ligand gated ion channel there is…

A

a GPCR for the same NT

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13
Q

Define PAR receptor

A

Protein activated receptor for thrombin

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14
Q

PAR receptor mechanism

A
  1. thrombin cleaves N terminus
  2. The remaining N terminus folds into the ligand BS to activate integrin
  3. Integrin binds to fibrinogen which causes the crosslinking and aggregation of platelets
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15
Q

What other receptor is required in blood clotting

A

ADP receptor (GPCR) detects ADP released from platelets

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16
Q

Positive allosteric modification define

A

Small molecule doesn’t bind to BS but influences stabilisation of TMD to control R

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17
Q

Basic pathway in GPCR signalling (8 steps)

A
  1. Agonist binds
  2. TM 3 detect
  3. TM5/6 move to reveal binding pocket (IC TM3/5/6)
  4. When inactive alpha high affinity for GDP = GDP bound
  5. when agonist bound, active conf so alpha binds to pocket exposed so GDP dissoc, GTP assoc
  6. beta gamma dissoc –> effectors
  7. alpha = enzyme, hydrolyses GTP
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18
Q

Monomeric G protein properties and example

A

RAS
Inactive protein locked in GDP bound state - GEF –> conf change for GDP dissoc, GTP assoc
GAP proteins control timing of GTPase activity

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19
Q

Heterotrimeric G protein properties

A

Agonist bound to R acts like GEF –> GDP dissoc, GTP assoc

RGS proteins control GTPase activity

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20
Q

Example of RGS protein

A

Phospholipase C

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21
Q

What distinguishes GPCRs

A

alpha subunit - all interact R same way but different effector pathways

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22
Q

Receptor and effector of Gia

A 
Receptors:
alpha-adrenergic amines
NT
Ach
chemokines
tastants

Effectors:
inhib adenylyl cyclase
open K+ channels
close Ca2+ channels

23
Q

Receptor and effector of Gqa

A

Receptors:
alpha-adrenergic amines
NT
Ach

Effectors:
Activate Phospholipase C
this produces IP3
this release Ca2+

24
Q

Receptor and effector of Gsa

A

Receptors:
beta adrenergic amines
hormones

Effectors:
stimulate adenylyl cyclase –> cAMP –> R kinases

25
Receptor and effector of Gta
Receptors: rhodopsin absorbs light Effectors: Activates cGMP phosphodiesterase - breaks down cGMP --> R kinases
26
Receptor and effector of G13a
Receptor Thrombin Effector Rho
27
Golfa
Receptor Odorant Effector Activates adenylyl cyclase and R kinases
28
What is special about odorant receptors
They are all GPCRs with same trimeric G protein
29
How many trimeric G proteins
1000
30
Half life of G protein activity
15 sec
31
Duration of signaling by heterotrimeric G protein is regulated by what
rate of GTP hydrolysis by Ga
32
What stimulates GTPase activity
RGS
33
PLC beta works by...
- feedback as effector binds to alpha
34
Examples of 2 effectors of GPCRS
enzymes that gen 2nd messengers | ion channels
35
How are ion channels regulated by GPCRs
directly - beta gamma | indirectly - 2nd messengers
36
define 2nd messenger
small moleucles that carry a signal inside cells
37
Message of 2nd messengers is encoded by
conc, frequency of change of conc
38
Local conc of 2nd messengers determined by
Rate production/diffusion/removal
39
Adenylyl cyclase produces... by
cAMP from ATP in ms
40
Removal of adenylyl cyclase
Phosphodiesterase (Gia pathway)
41
How many genes/isoforms of adenylyl cyclase
10
42
How many phosphodiesterases
40 from 11 genes
43
What activates adenylyl cyclase
Cholera toxin Forskolin Gas
44
Structure of adenylyl cyclase
Membrane anchored protein
45
Input into Gia/Gsi for adenylyl cyclase
7 helix receptors
46
Briefly describe beta2 adrenoreceptor regulation
Metabolism of liver/skeletal muscle Gas --> increase adenylyl cyclase --> increase cAMP --> activate PKA --> sig cascade of phosphorylation and enzymes controlling glycogen metabolism
47
Beta2 adrenoreceptor regulation step 1 - 8
1. Agonist binds Gs-bound beta-adrenergic receptor 2. Activated receptor catalyses the exchange of GDP for GTP on Gs protein causing dissociation of GTP-bound Gs-α 3. Gs alpha subunit activates adenylyl cyclase to produce cAMP 4. cAMP activates protein kinase A (PKA) which mediates most effects of cAMP however in some pathways cAMP activates cyclic nucleotide-gated ion channels 5. Each PKA amplifies the signal by phosphorylating phosphorylase kinase 6. Phosphorylase kinase amplifies and act on phosphorylase B 7. The phosphorylase enzymes remove glucose units from glycogen 8. This makes G6P which is dephos and enter blood via liver or enters glycolytic pathway
48
Signalling is switched off by
1. agonist dissoc 2. GTPase activity of Gas 3. cAMP breakdown by phosphodiesterase 4. Dephos of enzymes
49
Where is there -ve feedback
PKA beta-arrestin (binds to R) GRK
50
Name 3 activating diseases and their defective receptor
Parathyroid Ca2+ sensor --> hypoparthyroidism Rhodopsin --> night blind Thyroid hormone R --> hyperthyroidism/cancer
51
Name 5 LOF diseases and their defective receptor
Parathyroid Ca2+ sensor --> hyperparthyroidism Rhodopsin --> pigment Degen/retinitis pigmentoda Thyroid hormone R --> hypothyroidism Cone cell opsin --> colour blind Vasopressin --> nephrogenic diabetes insipidus, kidneys don't absorb H2O
52
Name 2 GTPase excess signals disease and their defective receptor
Gsa --> cholera toxin inhibits ADP-ribosylation on R201 --> inhibt GTP hysrolysis intensines Gsa --> pituitary/thyroid adenomas --> somatic point mutation R201/Q227 inhibits GTP hydrolysis
53
Name 2 GTPase inhibitory signals disease and their defective receptor
Whooping cough - Gia - pertussis toxin ADP ribosyltation C347 - block R in bronchial epithelia Night blind - Gta - G38 germline point mutation Pseudohypothyroidism type 1a - loss of Gsa or point mutation in receptor

Cell and molecular extras (16 decks)

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