X-ray structure of the mammalian GIRK2 – βγ G protein complex

G protein-gated inward rectifier K(+) (GIRK) channels allow neurotransmitters, via G protein-coupled receptor stimulation, to control cellular electrical excitability. In cardiac and neuronal cells this control regulates heart rate and neural circuit activity. We present the 3.5 Å resolution crystal structure of the mammalian GIRK2 channel in complex with βγ G protein subunits, the central signaling complex that links G protein-coupled receptor stimulation to K(+) channel activity. Short-range atomic and long-range electrostatic interactions stabilize four βγ G protein subunits at the interfaces between four K(+) channel subunits, inducing a pre-open state of the channel. The pre-open state exhibits a conformation that is intermediate between the closed and constitutively active mutant, open conformations. The resultant structural picture is compatible with “membrane delimited” activation of GIRK channels by G proteins and the characteristic burst kinetics of channel gating. The structures also permit a conceptual understanding of how the signaling lipid PIP(2) and intracellular Na(+) ions participate in multi-ligand regulation of GIRK channels.