GPCRs 3 Flashcards
What happens when arrestin is phosphorylated by GRK?
AP-2 and clathrin are brought to the surface of the membrane.
What does clathrin do?
It forms a chain of other clathrin molecules down the membrane of the cell.
What happens when clathrin has formed a chain of molecules?
Invagination of the membrane occurs.
What involvement does dynamic have with clathrin?
It cleaves the top of the membrane to form a vlathrin coated vesicle.
What happens to the GPCR after the involvement of dynamin and clathrin?
The GPCR is endocytosed and internalised - it moves into the cell away from the cell surface. A clathrin-coated vesicle is formed.
What is the name of the intracellular store of GPCR vesicles?
Early endosomes.
What are the two fates of early endosomes?
Late endosome or lysosome.
What happens in the early endosome stage?
The agonist comes off the receptor and arrestin drops off
What determines the fate of an early endosome?
Depends on the receptor type - there are epitotes on the surface of the receptor.
What happens if a late endosome is formed?
The receptors are recycled back to the cell surface.
What happens if a lysosome is formed?
The receptor is degraded and the protein goes to the nucleus and is metabolised.
What is the first signal for the internalisation of the receptor?
Arrestin.
What significance does arrestin have in receptor internalisation?
As morphine does not have arrestin involved in their mechanisms, these mu-opioid receptors will not be internalised.
Which GPCRs are rapidly recycled?
Beta2, alpha, mu-opioid, D1.
Which receptors are degraded?
At1, neurotensin, P2Y, NK1, delta-opioid.
Is receptor internalisation beneficial or negative?
Beneficial for recycled receptors are resensitization is accelerated, bad for receptors that are lysosomed - prolonged loss of receptor function.
What is a receptor that is a target for anti-asthma drugs?
The beta-2 agonist.
Would beta-2 antagonists be beneficial for asthma?
No - reverse effect of agonists - but this is unclear.
What happens with consistent treatment of mice with asthma attacks with beta 2 antagonists?
They become asthma treatment and make symptoms better - they are inverse agonists not antagonists which explains the effect.
What are inverse agonists?
Agents that stabilise the inactive state of the receptor and prevent/reduce the probability of constitutive activation. There is a reduced probability of internalisation and receptor degradation.
What is the effect of inverse agonists?
More receptors are being inserted into the cell membrane (as they are constantly being produced), but degradation is inhibited. There is an overall increase in the number of receptors.
What is heterologous desensitization?
The activation of one receptor that can affect how the other one acts.
What is oligomerization?
When two or more receptors are physically linked.
What is the difference between a homodimer and heterodimer?
Homodimer - two of the same receptors oligomerizing, heterodimer - two different receptors oligomerizing.
What is unusual about GABAb receptors?
They only signal as heteromers.
How does GABAb form heteromers?
There are two subtypes that coil and physically attach themselves together. Receptor 1 binds GABA and doesn’t couple to the G protein, whereas receptor 2 can signal through the G protein but GABA cannot bind.
What is transactivation?
The concept that one receptor is activated by an agonist and the other dimer causes signalling of the G protein.
What are the ways in which heteromers can link?
N-terminal linking, contact dimer, domain swapped dimer.
What are the functional consequences of heterodimerization?
Altered signalling, altered pharmacology and altered desensitization/internalization.
What can delta-opioid antagonists be used for?
They can be linked to mu-opioid agonists to provide beneficial effects.
What benefits do delta-opioid antagonists provide when linked with a mu-opioid agonist?
They can increase the potency of and decrease the desensitization induced by mu-opioids. They cause less tolerance than the mu-opioid agonist alone.
What is a bivalent ligand?
One chemical made from two chemical entities linked together - mu opioid and delta opioid receptor.
