Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium.
G protein-gated K(+) channels (Kir3.1-Kir3.4) control electrical excitability in many different cells. Among their functions relevant to human physiology and disease, they regulate the heart rate and govern a wide range of neuronal activities. Here, we present the first crystal structures of a G protein-gated K(+) channel. By comparing the wild-type structure to that of a constitutively active mutant, we identify a global conformational change through which G proteins could open a G loop gate in the cytoplasmic domain. The structures of both channels in the absence and presence of PIP(2) suggest that G proteins open only the G loop gate in the absence of PIP(2), but in the presence of PIP(2) the G loop gate and a second inner helix gate become coupled, so that both gates open. We also identify a strategically located Na(+) ion-binding site, which would allow intracellular Na(+) to modulate GIRK channel activity. These data provide a structural basis for understanding multiligand regulation of GIRK channel gating.
PubMed ID: 21962516
PMC ID: PMC3243363
Article link: Cell.
Grant support: Howard Hughes Medical Institute , R01 GM043949-21 NIGMS NIH HHS , P30 EB009998 NIBIB NIH HHS , R01 GM043949 NIGMS NIH HHS
Genes referenced: kcnj3 kcnj5 kcnj6