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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
Q

Receptor and effector of Gta

A

Receptors:
rhodopsin absorbs light

Effectors:
Activates cGMP phosphodiesterase - breaks down cGMP –> R kinases

26
Q

Receptor and effector of G13a

A

Receptor
Thrombin

Effector
Rho

27
Q

Golfa

A

Receptor
Odorant

Effector
Activates adenylyl cyclase and R kinases

28
Q

What is special about odorant receptors

A

They are all GPCRs with same trimeric G protein

29
Q

How many trimeric G proteins

A

1000

30
Q

Half life of G protein activity

A

15 sec

31
Q

Duration of signaling by heterotrimeric G protein is regulated by what

A

rate of GTP hydrolysis by Ga

32
Q

What stimulates GTPase activity

A

RGS

33
Q

PLC beta works by…

A
  • feedback as effector binds to alpha
34
Q

Examples of 2 effectors of GPCRS

A

enzymes that gen 2nd messengers

ion channels

35
Q

How are ion channels regulated by GPCRs

A

directly - beta gamma

indirectly - 2nd messengers

36
Q

define 2nd messenger

A

small moleucles that carry a signal inside cells

37
Q

Message of 2nd messengers is encoded by

A

conc, frequency of change of conc

38
Q

Local conc of 2nd messengers determined by

A

Rate production/diffusion/removal

39
Q

Adenylyl cyclase produces… by

A

cAMP from ATP in ms

40
Q

Removal of adenylyl cyclase

A

Phosphodiesterase (Gia pathway)

41
Q

How many genes/isoforms of adenylyl cyclase

A

10

42
Q

How many phosphodiesterases

A

40 from 11 genes

43
Q

What activates adenylyl cyclase

A

Cholera toxin
Forskolin
Gas

44
Q

Structure of adenylyl cyclase

A

Membrane anchored protein

45
Q

Input into Gia/Gsi for adenylyl cyclase

A

7 helix receptors

46
Q

Briefly describe beta2 adrenoreceptor regulation

A

Metabolism of liver/skeletal muscle

Gas –> increase adenylyl cyclase –> increase cAMP –> activate PKA –> sig cascade of phosphorylation and enzymes controlling glycogen metabolism

47
Q

Beta2 adrenoreceptor regulation step 1 - 8

A
  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
Q

Signalling is switched off by

A
  1. agonist dissoc
  2. GTPase activity of Gas
  3. cAMP breakdown by phosphodiesterase
  4. Dephos of enzymes
49
Q

Where is there -ve feedback

A

PKA
beta-arrestin (binds to R)
GRK

50
Q

Name 3 activating diseases and their defective receptor

A

Parathyroid Ca2+ sensor –> hypoparthyroidism

Rhodopsin –> night blind

Thyroid hormone R –> hyperthyroidism/cancer

51
Q

Name 5 LOF diseases and their defective receptor

A

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
Q

Name 2 GTPase excess signals disease and their defective receptor

A

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
Q

Name 2 GTPase inhibitory signals disease and their defective receptor

A

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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