Mutual action by G? and G? for optimal activation of GIRK channels in a channel subunit-specific manner.

ABSTRACT: The tetrameric G protein-gated K+ channels (GIRKs) mediate inhibitory effects of neurotransmitters that activate Gi/o-coupled receptors. GIRKs are activated by binding of the G?? dimer, via contacts with G?. G? underlies membrane targeting of G??, but has not been implicated in channel gating. We observed that, in Xenopus oocytes, expression of G? alone activated homotetrameric GIRK1* and heterotetrameric GIRK1/3 channels, without affecting the surface expression of GIRK or G?. G? and G? acted interdependently: the effect of G? required the presence of ambient G? and was enhanced by low doses of coexpressed G?, whereas excess of either G? or G? imparted suboptimal activation, possibly by sequestering the other subunit "away" from the channel. The unique distal C-terminus of GIRK1, G1-dCT, was important but insufficient for G? action. Notably, GIRK2 and GIRK1/2 were not activated by G?. Our results suggest that G? regulates GIRK1* and GIRK1/3 channel's gating, aiding G? to trigger the channel's opening. We hypothesize that G? helps to relax the inhibitory effect of a gating element ("lock") encompassed, in part, by the G1-dCT; GIRK2 acts to occlude the effect of G?, either by setting in motion the same mechanism as G?, or by triggering an opposing gating effect.

SUBMITTER: Tabak G 

PROVIDER: S-EPMC6346094 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature