Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium

Cell. 2011 Sep 30;147(1):199-208. doi: 10.1016/j.cell.2011.07.046.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / chemistry*
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics
  • GTP-Binding Proteins / metabolism
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Sequence Alignment
  • Sodium / metabolism
  • Xenopus laevis

Substances

  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Phosphatidylinositol 4,5-Diphosphate
  • Sodium
  • GTP-Binding Proteins

Associated data

  • PDB/3SYA
  • PDB/3SYC
  • PDB/3SYO
  • PDB/3SYP
  • PDB/3SYQ