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Missed Lectures > GPCR > Flashcards

GPCR Flashcards

1
Q

What is transduction?
Give an example of it.

A

The response/ outcome of a ligand binding to a receptor.
This could be contraction, secretion, proliferation, differentiation, etc.

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2
Q

What are the 3 superfamilies of cell-surface receptor?

A

G-protein coupled receptors.
Ligand-gated ion channels.
Enzyme-lined receptors, like tyrosine kinases.

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3
Q

Give a few examples of endogenous and exogenous ligands that bind to Adrenoreceptors.

A

Endogenous = noradrenaline and adrenaline.
Exogenous = salbutamol and propranolol.

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4
Q

Outline what an agonist is and give a pharmacological example.

A

An agonist is a molecule that binds to a receptor and activates it.

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5
Q

Outline what an antagonist is and give an example.

A

An antagonist is a molecule that binds to a receptor (has affinity), and blocks the effects of agonists (no efficacy).

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6
Q

What are the common basic structure of GPCRs?

A
  • Single polypeptide chain.
  • 7 transmembrane domains.
  • Extracellular N-terminal.
  • Intracellular C-terminal.
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7
Q

What are the different signal types that GPCRs can respond to?

A

Ions.
Neurotransmitters.
Hormones.
Glycoproteins.
Sensory GPCRs can also respond to light, odours and tastes.

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8
Q

What are the two binding sites of GPCRs?

A

Within the transmembrane domains.
On the extracellular N-terminal.

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9
Q

What is a G-protein?

A

It is a guanine-nucleotide binding protein.
It is made up of 3 subunits:
- alpha.
- beta.
- gamma.
This makes it a heterotrimeric protein.

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10
Q

How are G-proteins bound to the lipid bilayer?

A

Through lipid anchored proteins.
The alpha subunit is attached by a lipid anchored protein, and the beta and gamma subunit is attached by a different lipid anchored protein.

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11
Q

Outline the changes that occur from the binding of the ligand.

A

A ligand binds to the binding site on the N terminal or transmembrane domains.
This stimulates the 7 transmembrane domains to undergo a conformational change.
The conformational change increases the affinity for the G-protein for the transmembrane domains.
By binding to the transmembrane domains, the G-proteins become activated.

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12
Q

Outline how the G-proteins cause intracellular changes.

A

In the basal state, the alpha subunit is bound to by the beta-gamma subunit with high affinity, due to the binding of a GDP molecule.
The activation of the G-protein, by binding to the transmembrane domain stimulates the exchange of a GDP molecule for a GTP molecule.
This causes the alpha subunit to separate from the beta-gamma subunits.
Once separated, they can each cause their own effects, by interacting with effector proteins.

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13
Q

Outline how the effects of G-proteins are terminated.

A

The alpha-subunit contains a GTPase protein.
This slowly hydrolyses the GTP molecule, into GDP (around 5 seconds).
Once the hydrolysis is complete, there is an increased affinity for the beta-gamma subunits.
Once bound, their effects stop.

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14
Q

What governs the different effects that GPCRs can have?

A

The different alpha-subunit that is associated within the complex.

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15
Q

State the main 3 types of alpha-subunit GPCRs.

A

Gs.
Gi.
Gq.

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16
Q

Outline how G-alpha-s GPCRs produce their effect.
State what kind of receptor they are normally found on.

A

The binding of the ligand to the receptor activates the G-alpha-s protein.
This stimulates adenylyl cyclase to increase levels of cAMP, which activates protein kinase A (PKA).
PKA can then phosphorylate multiple proteins to increase or decrease activity.

They are normally beta-adrenoreceptors.

17
Q

Outline how G-alpha-i normally produce their effects.
State what kind of receptor they are normally found on.

A

The binding of a ligand to the receptor activates the G-alpha-i protein.
This inhibits the activity of the adenylyl cyclase, reducing the concentration of cAMP.

They are normally alpha2-adrenoreceptors and M2 receptors.

18
Q

Outline how G-alpha-q normally produce their effects.
State which kind of receptor they are normally found on.

A

The binding of a ligand to the receptor activates the G-alpha-q protein.
This stimulates phospholipase C, which generates IP3 and DAG.

These are normally found associated to alpha1-adrenoreceptors, M1 and M3 receptors.

19
Q

Complete the table:

A
20
Q

Explain how cholera toxin interacts with the GPCR effects.

A

The cholera toxin modifies the G-alpha-s subunit.
This modification inhibits the activity of GTPase.
This means that the GTP is not broken down and so the effectors of the alpha-subunit, and the beta and gamma subunit continue their effects.

21
Q

Outline how the pertussis toxin inhibits GPCR effects.

A

The pertussis toxin inhibits the exchange of GDP for GTP, through covalent modification of the G-alpha-i subunit.
This means that the alpha-subunit never dissociates from the beta and gamma subunit.
This means that the effectors cannot occur.

22
Q

What two types of molecules can effectors be?

A

Enzymes or ion channels.

23
Q

How do G-alpha-s GPCRs cause their effect?

A

The binding of a ligand to the transmembrane domain stimulates a conformational change to occur, activating the alpha-s subunit.
The activated subunit exchanges the GDP for GTP.
The exchange stimulates the alpha-s subunit to dissociate from the beta-gamma subunit.
The alpha-s subunit then activates the adenylyl cyclase.
The adenylyl cyclase then converts ATP to cAMP.
cAMP then activates PKA, which can then go on to phosphorylate cellular proteins.

24
Q

Give some examples of G-alpha-s associated receptors.

A

Beta-adrenoreceptors.
D1-dopamine receptors.
H2-histamine receptors.

25
Q

Explain how cyclic AMP activates PKA.

A

PKA is made up of 2 regulatory subunits and 2 catalytic subunits.
4 cAMP molecules bind to the regulatory subunits, allowing the dissociation of the catalytic subunits.

26
Q

Give some examples of G-alpha-i coupled receptors.

A

Alpha2-adrenoreceptors.
D2-dopamine receptors.
u-opioid receptors.

27
Q

Explain how G-alpha-i receptors work.

A

A ligand binds to the transmembrane domains, causing a conformational change to occur.
This conformational change activates the alpha-i subunit, causing it to exchange its GDP for GTP.
Once the GTP is bound, it dissociates from the beta-gamma subunit.
It then acts on the adenylyl cyclase to inhibit the production of cAMP.

28
Q

Give some examples of G-alpha-q coupled receptors.

A

Alpha-1 adrenoreceptors.
M1-muscarinic receptors.
H1-histamine receptors.

29
Q

Explain how G-alpha-q receptors achieve their desired outcome.

A

The binding of a ligand to the GPCR stimulates a conformational change, activating the alpha-q subunit.
This stimulates the alpha-q subunit to exchange its GDP for GTP.
This dissociates the alpha-q subunit from the beta-gamma subunit.
The alpha-q subunit then acts on phospholipase C, which cleaves PIP2 into IP3 and DAG.
IP3 then activates the LGCC on the endoplasmic reticulum, releasing intracellular calcium.
DAG activates PKC, which can then phosphorylate intracellular proteins.

30
Q

Explain the importance of signal amplification.

A

A small number of ligands are required to produce a large intracellular response.

31
Q

Explain how adrenaline/ noradrenaline increases contractility of the heart.

A

Adrenaline/ noradrenaline bind to Beta-1 adrenoreceptors, which are associated to G-alpha-s proteins.
The binding of these ligands causes a conformational change in the receptor, activating the alpha-s subunit.
The alpha-s subunit then exchanges GDP for GTP, stimulating it to dissociate from the beta-gamma subunit.
The alpha-s subunit can then activate adenylyl cyclase to produce more cAMP from ATP.
This cAMP activates PKA, which then phosphorylates the VGCC.
The phosphorylation of the VGCC increases the opening probability, so more calcium can flow into the cell.
The increase in intracellular calcium stimulates the sarcoplasmic reticulum to further release more calcium, stimulating a greater force of contraction.

32
Q

What is an increase in the opening probability?

A

It is where there needs to be a smaller depolarisation to allow the opening of the ion channel, so there is a greater influx/ efflux of the ion.

33
Q

Explain how nor/adrenaline causes vasoconstriction to occur.

A

The alpha1-adrenoreceptors are G-alpha-q associated. This means that the binding of noradrenaline causes a conformational change in the alpha1-adrenoreceptor.
This conformational change activates the alpha-q subunit, stimulating the exchange of GDP for GTP.
The alpha-q subunit then dissociates from the beta-gamma subunit.
The alpha-q subunit then acts on phospholipase C, activating it to cleave PIP2 to IP3 and DAG.
The IP3 then stimulates calcium release from the sarcoplasmic reticulum.
This calcium binds to calmodulin, which then activates the MLCK, which phosphorylates the myosin light chain.
Phosphorylation of the myosin light chain activates the myosin head, allowing it to interact with the actin filaments and to contract.
The DAG activates PKC, which phosphorylates the myosin light chain phosphatase.
This means that the myosin light chain is not de-phosphorylated and can continue to contract.

34
Q

Explain how u-opioid receptors work in inhibiting pain felt.

A

U-opioid receptors are pre-synaptic G-alpha-i coupled receptors.
The binding of a ligand, such as morphine, to the u-opioid receptor stimulates a conformational change to occur.
This conformational change stimulates the alpha-i subunit to exchange its GDP for GTP.
This exchange stimulates the dissociation between the alpha-i and beta-gamma subunits.
The beta-gamma subunit then inhibits the VGCC, preventing calcium influx into the cell.
This means that there are less vesicles stimulated to reach the pre-synaptic membrane and so less neurotransmitter is released.
Therefore, there is less pain signalling received.

35
Q

What does the mnemonic QISS QIQ stand for, and state their effectors.

A
36
Q

Explain how GPCR effects are controlled.

A

The alpha subunits have an enzyme GTPase, which hydrolyses the GTP to terminate the effects of the alpha and beta-gamma subunits.
The association of a receptor with an alpha-subunit decreases the affinity for a ligand.
The receptor is prone to phosphorylation, meaning that it cannot continue to activate other G-proteins.
There is often a downstream counter-mechanism for the effects of the kinase, such as a phosphatase.
The receptors are also highly specific and often require multiple ligands to activate them.

37
Q

What effect can G-alpha-s GPCRs have on metabolism?

A

Increased lipolysis in adipose, and glycolysis and gluconeogenesis in the liver

38
Q

Explain how heart rate is controlled.

A

The SA node controls the rate of depolarisation.
The SA node is controlled by acetylcholine acting on it, which is released by parasympathetic nerves.
The M2 muscarinic receptors are associated with G-alpha-i proteins, and so the binding of ACh causes a conformational change of the receptor, activating the alpha-i subunits.
The alpha-i subunits (and possibly the beta-gamma subunits) act on the VG potassium channels to increase the open probability of them.
This means that there is a greater influx of potassium, hyperpolarising the cardiac myocytes, slowing the depolarisation and speed of the heart.

Missed Lectures (13 decks)

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