N- and C-terminal domains87. Systematic mutagenesis studies have indicated that specific amino acids in the M2 transmembrane domain88-90 and G-loop65,67,68 form a barrier to ion conduction in the closed state; thus conformational changes triggered in the cytoplasmic domains must couple to the channel’s gates to open the channel. For example, the binding of Gβγ subunits to the channel could induce a conformational change involving the βL-βM sheets (containing the Leu implicated in Gβγ activation), the N-terminal domain, and the slide-helix, which, in turn, is relayed to the M2 and G-loop gates near the membrane. High-resolution structures of Gβγ or Gαβγ complexed with full-length GIRK channels will be necessary to clarify our understanding of the molecular and structural mechanism underlying Gβγ activation and to identify amino acids in the Gβγ and Gα subunits that interact with GIRKs.
