Mutual Action By G Gamma And G Beta For Optimal Activation Of Girk Channels In A Channel Subunit-Specific Manner

The tetrameric G protein-gated K+ channels (GIRKs) mediate inhibitory effects of neurotransmitters that activate G(i/o)-coupled receptors. GIRKs are activated by binding of the G beta gamma dimer, via contacts with G beta. G gamma underlies membrane targeting of G beta gamma, but has not been implicated in channel gating. We observed that, in Xenopus oocytes, expression of G gamma alone activated homotetrameric GIRK1* and heterotetrameric GIRK1/3 channels, without affecting the surface expression of GIRK or G beta. G gamma and G beta acted interdependently: the effect of G gamma required the presence of ambient G beta and was enhanced by low doses of coexpressed G beta, whereas excess of either G beta or G gamma 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 gamma action. Notably, GIRK2 and GIRK1/2 were not activated by G gamma. Our results suggest that G gamma regulates GIRK1* and GIRK1/3 channel's gating, aiding G beta to trigger the channel's opening. We hypothesize that G gamma 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 gamma, either by setting in motion the same mechanism as G gamma, or by triggering an opposing gating effect.