Crystal Structure of the Mammalian GIRK2 K+ Channel and Gating Regulation by G Proteins, PIP2, and Sodium

Laboratory of Molecular Neurobiology and Biophysics, Rockefeller University, New York, NY 10065, USA.
Cell (Impact Factor: 32.24). 09/2011; 147(1):199-208. DOI: 10.1016/j.cell.2011.07.046
Source: PubMed


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.

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    • "Through direct interactions, PIP2 modulates the functions of many ion channels (inwardrectifier and voltage-gated K + channels, voltage-gated Ca 2+ channels, cyclic nucleotide-gated channels, etc.) [39-41], and PIP2 has also emerged as a versatile regulator of TRPs [22] [23]. The atomic-level description of the molecular mechanism by which PIP2 regulates channel activity, as well as how PIP2 induces conformation changes in the protein, was determined from crystal structures of a K + channel/PIP2 complex [42] [43]. Apart from the similar general architecture of TRPs, PIPs are likely to be the only common factor regulating these proteins. "

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    • "This is consistent with PIP2 stabilizing the open gate conformation through a mechanism similar to the one described for Kir channels (Hansen, Tao & MacKinnon, 2011; Whorton & MacKinnon, 2011). "
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