Mutual action by Gγ and Gβ 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 Gβγ dimer, via contacts with Gβ. Gγ underlies membrane targeting of Gβγ, but has not been implicated in channel gating. We observed that, in Xenopus oocytes, expression of Gγ alone activated homotetrameric GIRK1* and heterotetrameric GIRK1/3 channels, without affecting the surface expression of GIRK or Gβ. Gγ and Gβ acted interdependently: the effect of Gγ required the presence of ambient Gβ and was enhanced by low doses of coexpressed Gβ, whereas excess of either Gβ or Gγ 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 Gγ action. Notably, GIRK2 and GIRK1/2 were not activated by Gγ. Our results suggest that Gγ regulates GIRK1* and GIRK1/3 channel's gating, aiding Gβ to trigger the channel's opening. We hypothesize that Gγ 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 Gγ, either by setting in motion the same mechanism as Gγ, or by triggering an opposing gating effect.