GPCR Flashcards
What is transduction?
Give an example of it.
The response/ outcome of a ligand binding to a receptor.
This could be contraction, secretion, proliferation, differentiation, etc.
What are the 3 superfamilies of cell-surface receptor?
G-protein coupled receptors.
Ligand-gated ion channels.
Enzyme-lined receptors, like tyrosine kinases.
Give a few examples of endogenous and exogenous ligands that bind to Adrenoreceptors.
Endogenous = noradrenaline and adrenaline.
Exogenous = salbutamol and propranolol.
Outline what an agonist is and give a pharmacological example.
An agonist is a molecule that binds to a receptor and activates it.
Outline what an antagonist is and give an example.
An antagonist is a molecule that binds to a receptor (has affinity), and blocks the effects of agonists (no efficacy).
What are the common basic structure of GPCRs?
- Single polypeptide chain.
- 7 transmembrane domains.
- Extracellular N-terminal.
- Intracellular C-terminal.
What are the different signal types that GPCRs can respond to?
Ions.
Neurotransmitters.
Hormones.
Glycoproteins.
Sensory GPCRs can also respond to light, odours and tastes.
What are the two binding sites of GPCRs?
Within the transmembrane domains.
On the extracellular N-terminal.
What is a G-protein?
It is a guanine-nucleotide binding protein.
It is made up of 3 subunits:
- alpha.
- beta.
- gamma.
This makes it a heterotrimeric protein.
How are G-proteins bound to the lipid bilayer?
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.
Outline the changes that occur from the binding of the ligand.
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.
Outline how the G-proteins cause intracellular changes.
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.
Outline how the effects of G-proteins are terminated.
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.
What governs the different effects that GPCRs can have?
The different alpha-subunit that is associated within the complex.
State the main 3 types of alpha-subunit GPCRs.
Gs.
Gi.
Gq.
Outline how G-alpha-s GPCRs produce their effect.
State what kind of receptor they are normally found on.
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.
Outline how G-alpha-i normally produce their effects.
State what kind of receptor they are normally found on.
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.
Outline how G-alpha-q normally produce their effects.
State which kind of receptor they are normally found on.
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.
Complete the table:
Explain how cholera toxin interacts with the GPCR effects.
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.
Outline how the pertussis toxin inhibits GPCR effects.
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.
What two types of molecules can effectors be?
Enzymes or ion channels.
How do G-alpha-s GPCRs cause their effect?
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.
Give some examples of G-alpha-s associated receptors.
Beta-adrenoreceptors.
D1-dopamine receptors.
H2-histamine receptors.
