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Pharmacology 3 > L7: Intracellular Mechanisms of GPCR signalling > Flashcards

L7: Intracellular Mechanisms of GPCR signalling Flashcards

1
Q

What are the 4 main families of GPCRs according to phylogenic analysis?

A
  • Glutamate,
  • Rhodopsin,
  • Frizzled,
  • Secretin
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2
Q

What are the Membrane Resident Proteins in GPCRs?

A

G protein, middle messenger between receptor and effector

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3
Q

What are effector systems in GPCRs signalling?

A

Second messengers

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4
Q

What is the function of G-proteins in GPCRs signalling?

A
  • To recognise activated GPCRs
  • pass on the message to effector systems
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5
Q

Which part of GPCRs is coupled to G-proteins during signalling?

A

Long 3rd cytoplasmic loop couples to G-protein

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6
Q

What do G-proteins interact with?

A

G-proteins interact with Guanine nucleotides (GTP; GDP)

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7
Q

How many subunits G-proteins have and where are they located in the cell?

A

All 3 subunits bound of G-proteins are bound to the cell membrane

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8
Q

Does single pool of G-proteins interact with only one receptor?

A

Single pool of G-proteins can interact with several different receptors

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9
Q

In which subunit of G-proteins is GTPase domain?

A

GTPase is in alpha-subunit

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10
Q

What is the function of GTPase domain of G-proteins?

A
  • Hydrolyses GTP
  • provides binding surface for G-beta-gamma GPCRs and effector proteins
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11
Q

Shortly describe beta-gamma subunit of G-proteins

A

Tight functional unit, only dissociated by denaturation

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12
Q

What is ‘collision coupling’ regarding GPCRs?

A

The collision coupling model describes interactions between receptors and G-proteins as first requiring the molecules to find each other by diffusion.

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13
Q

Describe G-proteins in resting state.

A

G-protein trimer unattached, GDP occupying alpha-subunit

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14
Q

Describe the changes in GPCRs and G-proteins followed by occupied receptor

A

1) conformational change in cytoplasmic domain; high affinity for alpha-beta-gamma
2) GDP dissociates from alpha-subunit of G-proteins
3) GDP replaced by GTP
4) G-protein trimer dissociates
5) ‘active’ forms of the G-protein diffuse in the membrane
6) associate with enzymes / ion channels; activates targets

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15
Q

What is the function of beta-gamma subunit of G-proteins?

A

Beta-gamma subunit of G-proteins is considered a chaperone, controls effect but higher concentrations required.
As for Gi/o, also:
- activates potassium channels
- inhibits VGCCs (voltage-gated calcium channels)
- activates GPCR kinases (GRKs)
- activates MAP kinase cascade

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16
Q

What happens to G-proteins upon signal termination of GPCRs?

A
  • attachment of a subunit to target increases its GTPase activity
  • hydrolysis of GTP to GDP
  • alpha-subunit moves back
  • returns to homeostasis
17
Q

How does a single pool of G-proteins allow each receptor to produce a distinct cellular response?

A

It’s not a single entity, molecular variation within subunits, >20 subtypes, 4 main classes: Gs, Gi/o, G12/13, Gq

18
Q

What is the function of Gs class of G-proteins?

A

Adenylate Cyclase, stimulation, Increasing cAMP

19
Q

What is the function of Gi/o class of G-proteins?

A

Adenylate Cyclase, inhibition, decreasing cAMP

20
Q

What is the mechanism of Adenylate Cyclase?

A
  • adenylate cyclase converts ATP to cAMP
  • cAMP then converts PKi to PKa
  • PKa phosphorylates the protein

CHECK L7, slide 18 for diagramm

21
Q

How can levels of cAMP be reduced?

A

cAMP can be converted to 5’-AMP by PDEs (hydrolysis reaction), which reduces cAMP levels meaning that PKi conversion to PKa is obstructed, thus no protein phosphorylation.

22
Q

Explain the mechanism of Adenylate Cyclase in smooth muscle by the action of isoprenaline

A

FOR DIAGRAMM check L7, slide 20
1) beta-adrenergic receptor is activated by isoprenaline
2) G-alpha-s dissociates and attaches to adenylate cyclase
3) adenylate cyclase converts ATP to cAMP
4) cAMP works on PKi conversion to PKa
5) PKa phosphorylates MLCK
6) MLCK-P becomes inactive, thus prevents muscle contraction
7) result - relaxed muscles

23
Q

Explain the mechanism of Adenylate Cyclase in smooth muscle by the action of clonidine

A

FOR DIAGRAMM check L7, slide 21
1) alpha-2-adrenergic receptor is activated by clonidine
2) G-alpha-i dissociates and attaches to adenylate cyclase
3) adenylate cyclase is inhibited
4) no cAMP to work on PKi conversion to PKa
5) MLCK does not get phosphorylated, thus it’s active
6) result - muscle contraction

24
Q

What is the function of Phosphodiesterase (PDEs) Inhibitors? Give example of inhibiting PDEs

A

Inhibit cAMP by hydrolysis to 5’-AMP, for example PDE4 produced by inflammatory cells inhibits cAMP, causing contractions. They can be inhibited, rolipram is used during asthma, it inhibits PDE4 to reduce secretion

25
Q

Explain the mechanism of Phospholipase C upon GPCRs activation

A

1) agonist binds GPCR (alpha-1 adrenergic receptor)
2) G-alpha-q dissociates from G-protein trimer
3) it attaches to Phospholipase C-beta (PLC-beta)
4) PLC-beta binds to its substrate PIP2
5) PIP2 is split in diacylglycerol (DAG; membrane bound) and IP3 (water soluble)
6) IP3 then binds to IP3R (ligand-gated calcium channel) on ER

26
Q

What is the function of IP3 upon Phospholipase C activation in GPCRs?

A

IP3 binds to IP3R (ligand-gated calcium channel) on ER to cause calcium release (intracellular conc increase of Ca2+ causes muscle contraction)

27
Q

What is the function of DAG upon Phospholipase C activation in GPCRs?

A

DAG is highly lipophilic so it stays in the membrane. It attaches to PKCa in the membrane which get converted to PKCi. PKCi then binds to a protein and phosphorylates it. It also acts as a proliferative factor.

28
Q

Why does ACh sometimes relax blood vessels?

A

ACh acts on M3 muscarinic receptors, which activate Gq G-protein. DAG then activates PKCa to PKCi, which phosphorylates the protein causing relaxation.

29
Q

How can ACh have opposite effects on smooth muscle contraction?

A

Depends on which cells ACh acts in tissue. If acts on endothelium, calcium first acts on L-Arg conversion, which produces tocix gas NO, then NO acts on GC (guanylate cyclase) in smooth muscle causing relaxation.
If ACh acts directly on smooth muscle then calcium causes contraction.
CHECK L7, slide 30

30
Q

What is the mechanism of action of Guanylate Cyclase in GPCRs activation?

A
  • GTP gets converted to cGMP
  • cGMP produces PKG
  • PKG causes relaxation of muscle
31
Q

How can cGMP be inhibited? Give an example

A

PDEs hydrolyse cGMP to 5’-GMP. Sildenafil (Viagra) prevents degradation of cGMP, it results in relaxation of blood vessels, higher blood flow

32
Q

Check L7, slide 34 for summary

A

Pharmacology 3 (21 decks)

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