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Molecular Pharmacology > GPCRs > Flashcards

GPCRs Flashcards

1
Q

What is the structure of a GPCR

A

7 transmembrane proteins in a single chain.3 intra and 3 extra cellular loopsN-terminus extracellularC-terminus intracellular

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2
Q

Name the 5 families of GPCRs

A

SecretinAdhesionGlutamateFrizzled/Taste2Rhodopsin

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3
Q

What is the special feature of the Adhesion family of GPCRs

A

Large N-terminus which includes similar regions to adhesion molecules

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4
Q

What are the special features of the Glutamate family of GPCRs

A

Mainly neuronalSmaller extracellular regionCan be ligand gated ion channels

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5
Q

What are the special features of the Frizzled/Taste2 family of GPCRs

A

Generally involved in controlling development and cell growth

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6
Q

What are the special features of the Rhodopsin family of GPCRs

A

Biggest family of GPCRs. Include amine receptors, light receptors, olfactory receptors etc.

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7
Q

How was the structure/function relationship of GPCRs determined?

A

They created chimeras. Fused two different receptors and measured response

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8
Q

What region of a GPCR determines function

A

Function is usually controlled by intracellular loops.Specifically intracellular loop 3 and carboxyl (C)-terminus.

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9
Q

How does a GPCR signal?

A

Receptor activation causes the alpha subunit of the G-protein to exchange a GDP for a GTP. The GTP bound alpha subunit is able to activate an effector molecule

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10
Q

How does a GPCR signal switch off

A

Each G-protein has an intrinsic GTPase. It hydrolyses the GTP to give GDP (inactive)

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11
Q

What are the 4 stages of the G-protein cycle

A

Basal stateReceptor activationEffector modulationGTP hydrolysis

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12
Q

What happens in the basal state of the G-protein cycle

A

Nothing. Alpha bound to GDP

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13
Q

What happens in the receptor activation state of the G-protein cycle

A

Agonist activates receptorG-protein coupled and GDP exchanged for GTPG-protein subunits dissociated

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14
Q

What happens in the effector modulation state of the G-protein cycle

A

Effector is bound to the G alpha subunit

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15
Q

What happens in the GTP hydrolysis state of the G-protein cycle

A

GTP bound to alpha subunit dissociates.Alpha G protein bound to GDPSubunits re-associate

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16
Q

What is the role of the alpha subunit of a G-protein

A

Bound to GDP/GTPActivates effector molecule

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17
Q

What is the role of the beta subunit of a G-protein

A

Propeller structure that creates stability

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18
Q

What makes up a G-protein

A

Alpha subunitBeta subunitGamma subunit

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19
Q

What is the effector pair of a Gs protein

A

Adenylate cyclase

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20
Q

What is the effector pair of a G (alpha i) protein

A

Adenylate cyclase

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21
Q

What is the effector pair of a G (alpha o) protein

A

K+ and Ca2+ channels

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22
Q

What is the effector pair of a G (alpha t) protein

A

cGMP phosphodiesterase

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23
Q

What is the effector pair of a G (alphah gust) protein

A

cGMP phosphodiesterase and possibly adenylate cyclase

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24
Q

What is the effector pair of a G (q / 11) protein

A

Phospholipase C - beta

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25
Q

What is the effector pair of a G (12 / 13) protein

A

Rho AMisc small proteins

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26
Q

What are the main downstream signalling molecules associated with GPCRs

A

Adenylyl cyclasecAMPProtein Kinase A (PKA)PhosphodiesteraseRGS (regulator of G-protein signalling)

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27
Q

Name a common downstream signalling pathway

A

Adenylyl (adenylate) cyclase activation -> increased cAMP levels -> Increased PKA levels -> lots of intracellular pathways

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28
Q

How does cAMP activate protein kinase A

A

PKA is made up of four subunits - two catalytic subunits, and two regulatory subunits.cAMP binds to and mediates the dissociation of the regulatory subunits, enabling PKA to function.

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29
Q

What is Forskolin and why is it used?

A

It is a drug that increases the effect of GPCRs coupled to a Gs protein. Usually used in labs to show effects of adenylyl cyclase as it bypasses the need for GPCR activation

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30
Q

Give an example of a downstream event triggered by PKA activation

A

Calcium-handling proteins activated, increases force of contraction in the heart

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31
Q

Which G-proteins change intracellular levels of cAMP

A

Gs - increasesGi - decreases

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32
Q

Define phospholipase

A

An enzyme that hydrolyses phospholipids (e.g. cAMP) into fatty acids and other lipophilic substances

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33
Q

What are the three groups of Protein Kinase C

A

Calcium-dependent, DAG-activated (cPKC; conventional)Calcium-independent, DAG-activated (nPKC; novel)Calcium-independent, DAG-non-responsive (aPKC; atypical)

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34
Q

What does adenylyl cyclase do

A

Synthesises cAMP from ATP.

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35
Q

How is adenylate cyclase regulated by GPCRs

A

Gs alpha protein stimulates AC effector. (e.g. beta-adrenoceptor)Gi alpha protein inhibits AC effector (e.g. alpha2-adrenoceptor; and CB1 cannabinoid receptor)

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36
Q

What is the structure of adenylate cyclase (AC)

A

Two transmembrane domains; C terminus is bound to the N terminus of the other

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37
Q

How many isoforms of Adenylate Cyclase (AC) have been identified

A

9

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38
Q

How does adenylate cyclase act as a catalyst

A

The two cytoplasmic C-domains in the second transmembrane domain interact.

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39
Q

Where is the AC1 receptor located

A

Brain retina, adrenal medulla

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40
Q

Where is the AC3 receptor located

A

Olfactory neurones, brain, retina, heart, lung

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41
Q

Where is the AC8 receptor located

A

Brain

42
Q

How do the AC1, AC3 and AC8 receptors work

A

Activated by calcium/calmodulinInhibited by G[alphai] subunits (AC1 and AC3)Inhibited by G[betagamma] subunits (AC1)

43
Q

Where is the AC2 receptor located

A

Brain, olfactory tissue, lung

44
Q

Where is the AC4 receptor located

A

Widespread

45
Q

Where is the AC7 receptor located

A

Widespread

46
Q

How do the AC2, AC4 and AC7 receptors work

A

Activated by Protein Kinase C (PKC)Unaffected by calcium/calmodulin/G[alphai] (unlike AC1,3,8)Stimulated by G[betagamma] subunits

47
Q

Where are the AC5 and AC6 receptors located

A

Heart, Brain, Kidney

48
Q

How do the AC5 and AC6 receptors work

A

Inhibited by free calcium; unaffected by Calcium/calmodulinInhibited by protein kinase A (PKA) phosphorylationunaffected by G[betagamme] subunits

49
Q

Where is the AC9 receptor located

A

Testis/widespread

50
Q

How does the AC9 receptor work

A

Inhibited by:Calcium/calcineurinG[alphai] subunitsProtein Kinase C (PKC) phosphorylationUnaffected by G[betagamma] subunits

51
Q

What is the specific activity of Protein Kinase A

A

Acts as a serine/threonine kinase. Transfers terminal phosphate on ATP onto target. Involves esterification between phosphate group and serine/threonine.

52
Q

What is the consensus sequence recognised by Protein Kinase A

A

NH2 —- Arg-Arg-X-Ser/Thr-X

53
Q

What does CREB stand for

A

cAMP response element binding protein

54
Q

How does Protein Kinase A activation affect the heart? how?

A

Phosphorylates several calcium handling proteins. Increases force of contractions

55
Q

What is CREB

A

A transcription factor that regulates gene expression

56
Q

How does protein kinase A affect CREB

A

IndirectlyModifies other proteins that are able to promote/inhibit transcription

57
Q

What genes are targeted by Protein Kinase A activity

A

Phosphoenolpyruvate carboxykinase (PEPCK) (rate limiting in glyconeogenesis)AC8, c-fos, glutamate receptor, tyrosine hydroxylase (important in learning and memory)

58
Q

What does PIP2 stand for

A

phosphatidylinositol-4,5-bisphosphate

59
Q

How is PIP2 affected by GPCR receptor activated

A

GPCR q effector is phospholipase C. Phospholipase C cleaves PIP2 (yielding DAG and IP3)

60
Q

What does DAG stand for

A

Diacyl Glycerol

61
Q

What does IP3 stand for

A

Inositol-1,4,5-triphosphate

62
Q

How are DAG and IP3 formed

A

Through PIP2 cleavage by phospholipase C

63
Q

What does DAG do

A

Activates protein kinase C which then moves from the cytosol to the plasma membrane. PKC then phosphorylates other proteins.

64
Q

What does IP3 do

A

Stimulates calcium release from the ER by activating calcium-release channels in the ER membrane.

65
Q

Give some examples of protein kinase C inhibitors

A

Non-selective protein kinase inhibitors (H7, staurosporine etc)Selective inhibitors (calphostin C etc)

66
Q

What modifications can happen to IP3

A

Phosphorylated (to IP4/5/6)Sequentially dephosphorylated - eventually yields inositol (can be used to synthesise phosphatidylinositol PI)

67
Q

What signalling role does IP4 have

A

Can stimulate Calcium entry (activation of plasma membrane calcium channels maybe?)

68
Q

What does GAP stand for

A

GTPase Activating Proteins

69
Q

What does a GAP do, how

A

Promotes GTP hydrolysisInserts an amino acid which helps to stabilise the transition state.

70
Q

What does RGS stand for

A

Regulator of G-protein signalling

71
Q

What do RGS proteins do

A

Negative regulators of G protein signalling. Stimulate GTP hydrolysis. Are a type of GAPAccelerate the rate of GTP hydrolysis

72
Q

What does GEF stand for

A

Guanine Nucleotide Exchange Factors

73
Q

What do GEFs do

A

Promote GDP/GTP exchange

74
Q

What can act as a GEF

A

An activated GPCRAGS (activator of G-protein signalling)

75
Q

How many families of RGSs are there

A

2Modulators and integrators

76
Q

How does RGS4 work

A

GPCR modulatorReversibly associates with membranes via N terminus amphipathic alpha-helix.Targets specific GPCRsCan bind to PIP3, which blocks the RGS. (stimulated by G[beta/gamma] subunits)(inhibited by calcium/calmodulin)

77
Q

What is the molecular basis of calcium oscillations (RGS4/PIP3)

A

GPCR activates; intracellular Ca incRGS4 forms complex which shuts off Ca mobilisation (Ca dec)PIP3 binds to RGS4; inhibits; allows Ca mobilisation (Ca inc)Ca/Cam complex forms. Inhibits PIP3. RGS4 continues. (Ca dec).Lowered Ca; CaM deactivated. PIP3 able to rebind to RGS4. PROCESS CONTINUES

78
Q

What does PDE stand for

A

phosphodiesterase

79
Q

What are phosphodiesterases

A

Diverse family of enzymes.Degrade phosphodiester bond in cyclic nucleotices (cAMP, cGMP etc).

80
Q

Why are phosphodiesterases important

A

Can degrade cyclic nucleotides - Regulators of signal transduction mediated by these secondary messenger molecules.

81
Q

How many member of the PDE family are there

A

11 families (PDE1-11)Over 50 isoforms known

82
Q

What are the key structural features of the PDE family members

A

Conserved catalytic site (in the C-terminus)They have regulatory sites/interactions at the N terminus

83
Q

How are the members of the PDE family involved in signalling

A

Each can be inhibited or stimulated by PKA, PKG, cGMP (and one by calcium/calmodulin)They each have varying affinity for degrading a specific type of cyclic nucleotide (cAMP, cGMP etc).

84
Q

What is the molecular basis of Antiphasic calcium oscillations

A

cAMP increases = Calcium decrease (and vice versa)Activation of store-operated/voltage-gated calcium channels. Simulates Ca/CaM dependent PDE1 activation. Stimulates cAMP hydrolysis for duration of calcium increase. Anti-phasic because they do the opposite of each other. (PDE1 dependent)

85
Q

What is the molecular basis of Phasic calcium oscillations

A

cAMP increase = calcium increaseCalcium increase stimulates adenylyl cyclase to increase cAMP production. Calcium decrease causes cAMP hydrolysis by PKA-dependent PDE4 activity. Phasic because they do the same thing as each other. (PDE4 dependent)

86
Q

How can IP3 signals be terminated

A

Dephosphorylation to inositol (minus 3 phosphates)

87
Q

What is G protein uncoupling

A

Occurs when phosphorylated (by specific kinases and G-protein coupled receptor kinases (GRKs))GRKs interact with agonist activated GPCRs. GRK phosphorylation allows beta-arrestins to bind.Beta-arrestins uncouple GPCRs from G-proteins

88
Q

What do beta-arrestins do to GPCRs

A

Uncouple G-proteins, preventing activationCan target for internalisation in clathrin-coated vesicles.

89
Q

What happens to a GPCR when bound in a clathrin-coated vesicle

A

Internalised.Then either degraded (by lysosomes); or dephosphorylated and recycled back to the surface (GRK activity reversed).

90
Q

How does GPCR desensitisation occur

A

Constant GPCR stimulation leads to phosphorylation by GRK. This binds beta-arrestin which targets the GPCR for internalisation in a clathrin-coated vesicle. From here can be degraded (downregulation) or recycled.

91
Q

What is cholera toxin

A

Protein toxin that acts intracellularly to enzymatically disrupt GTPase activity of G[Salpha] and G[t].

92
Q

What is the structure of cholera toxin

A

Made up of A1, A2 and B subunits

93
Q

How does cholera toxin work

A

B subunits bind to cell surface. A2 subunit is an ‘adaptor piece’ which enables the A1 subunit to enter the cellA1 subunit binds to ARF6 (ADP-ribosylation factor 6). Disrupts GTPase activity.

94
Q

What is pertussis toxin

A

Protein toxin - responsible for whooping cough

95
Q

What is the structure of pertussis toxin

A

Made up of A subunits (S1)and B subunits (S2-5)S2/S4 and S3/S4 are dimers linked together by S5.

96
Q

How does pertussis toxin work

A

Released in inactive form. Binds to cell receptor and internalised. S1 subunit is pathogenic. Activated by many factors (including ATP and reducing agents).

97
Q

What is the mechanism of cholera toxin

A

Catalyses the transfer of ADP-ribose from NAD+ to an arginine residue on the G[Salpha] GTPase active site. This prevents GTP hydrolysis.Therefore the stimulatory G-protein is permanently activated (because no GTPase to switch off)

98
Q

What is the mechanism of pertussis toxin

A

Catalyses the transfer of ADP-ribose onto a cysteine residue of the inhibitor G[ialpha]. This makes the protein incapable of exchanging GDP for GTP. Therefore the inhibitory pathway is blocked (and stimulatory continues)

99
Q

What are the cellular effects of cholera toxin

A

G[Salpha] permanently activatedMassive increase of cAMP. PKA activatedActivates CFTR-mediated chloride efflux in gut epitheliaRapid loss of fluid in gut ensues.

100
Q

What are the cellular effects of pertussis toxin

A

G[ialpha] permanently inactivated. cAMP levels increase. Causes:Increased insulin secretion (and hypoglycemia)CoughReduced neutrophil/macrophage recruitment (immune)

101
Q

Why are GTP analogues used

A

Different analogues can cause different effects (such as perma activation or inhibition).Allows to detect a GPCR, and identify the pathway

102
Q

Give some examples of GTP analogues used

A

Gpp(NH)p - Guanosine-5’[betagamma-imido] triphosphate; leads to perma activationGDP/AIF4- (Aluminium fluoride). Activates G proteins. Commonly used.

Molecular Pharmacology (10 decks)

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