GPCRs Flashcards
what is the general structure of GPCRs?
- 7 transmembrane spanning regions
- amino terminus outside the cell, carboxy terminus inside the cell
- 3 extracellular loops and 3 intracellular loops
- lots of diversity in the ligand binding domain
what is the mechanistic basis for GPCR activation?
conformational change in the 6th transmembrane region, which is displaced by 6 angstroms and TM5 extends by 3A
what types of ligand do GPCRs respond to?
neurotransmitters, peptide hormones, non-peptide hormones and large glycoproteins
how are G proteins ‘molecular switches’?
in inactive state, GDP is bound
GDP for GTP exchange occurs to activate the G protein
G proteins have intrinsic GTPase activity on the a-subunit
GTP binding causes dissociation of the By subunits
GTP displacement is stimulated by GEFs
what is a GEF?
guanine nucleotide exchange factor. activated GPCRs act as GEFs. GEF activity is caused by a small sequence of amino acids that are normally obscured, but are exposed upon the shifting of TM6
what types of GPCRs are there?
G alpha S - activates adenylyl cyclase
G alpha I - inhibits adenylyl cyclase
G alpha Q - activates phospholipase C
G alpha T - mediates effects of rhodopsin
G beta gamma - activates K+ channels and inhibits GIRK
how does cholera toxin act?
inhibits G alpha S GTPase activity, causing adenylyl cyclase to be constitutively active
how does pertussis toxin act?
inhibits G alpha I, reversing suppression of adenylyl cyclase
how do GPCRs exert specificity?
each kind of receptor facilitates a certain kind of response
this is due to molecular variation in alpha subunits
subtypes show specificity with respect to the receptors they couple to
what are the targets of G proteins?
adenylyl cyclase - responsible for cAMP formation
phospholipase C - responsible for IP3 and DAG formation
ion channels
Rho A/Rho kinase - regulates activity of many signalling pathways, controlling cell growth and proliferation
how is GPCR signalling terminated?
- serine and threonines present on C-terminus
- GPCR kinase phosphorylates them, stopping intracellular domains from interacting with G proteins
- also creates a binding site for B-arrestin, brings clathrin
- invaginated by cell and degraded by lysosome or recycled
- causes desensitisation to the ligand
what are ligand gated ion channels?
ion conducting pores formed from a-helices
regulated by the shape of the subunits
can have intra or extracellular binding sites
