10. GPCRs Flashcards
how many TMS alpha helices in GPCRs
7
how many extra- and intracellular domain
what is each used for?
4 extracellular domains
- used to interact with stimulus
4 intracellular domains
- used to interact with G-proteins
GPCRs have an 8th alpha helix, where is this located
at the c-terminal end on the cytosolic side of the plasma membrane
what is the 8th alpa helix (H8) covalently bound to
a membrane phospholipid called palmitic acid
name 3 functions mediated by GPCRs
hormone action
hormone secretion
cell growth
what % of medicines exert their effects by influencing G-protein pathways
60%
give 2 examples of GPCRs
beta-adrenergic receptor
alpha adrenergic receptor
what hormone do beta-adrenergic receptors respond to
epinephrine (fight or flight hormone)
describe the structure of beta-adrenergic GPCRs
7 alpha helices that form a barrel structure
where on beta-adrenergic receptors does epinephrine bind
in the centre of the barrel
what happens when epinephrine binds to beta-adrenergic GPCRs
interacts with 15 specific amino acids on the TMS helices
= induces a conformational change - allows the receptor to activate the G-protein
the G-proteins involved in the beta-adrenergic pathway are what?
heterotrimeric
what does heterotrimeric mean?
composed of 3 different subunits: alpha, beta and gamma
which subunit on a g-protein can bind GDP or GTP
alpha subunit
what is the name of the GTP/GDP binding site on g-proteins
guanyl nucleotide binding site
describe the G-protein cycle
- inactive form = GDP is bound to the guanyl binding site
- epinephrine binds = conformational change - activating the G-protein
- GDP exchanged for GTP
- alpha subunit bound to GTP dissociates and carries out downstream signalling
- to switch off signalling GTP is hydrolysed back into GDP and alpha subunit recombines
- cycle continues
what does the alpha subunit-GTP complex bind to
adenylate cyclase
describe the structure of adenylate cyclase
12 TMS alpha helices
2 domains: 6 helices in each
each domain has a catalytic domain, what does this do?
converts ATP into cAMP
what does cAMP activate
protein kinase A
what does protein kinase A do?
increase lipid hydrolysis
decrease glycogen synthesis
protein kinase has 4 subunits,, what does each do?
2 catalytic subunits
2 regulatory subunits
what happens when cAMP binds to kinase A
cAMP binds to regulatory binding site causing conformational change - removes pseudo substrate from catalytic domains
= activates the protein kinase to phosphorylate downstream signalling intermediates
what do all g-protein alpha subunits have
intrinsic GTPase activity
