Molecular mechanisms mediating inhibition of G protein-coupled inwardly-rectifying K+ channels

Mol Cells. 2003 Feb 28;15(1):1-9.


Neuronal G protein-coupled inwardly-rectifying potassium channels (GIRKs, Kir3.x) can be activated or inhibited by distinct classes of receptors (Galphai/o and Galphaq/11-coupled, respectively), providing dynamic regulation of neuronal excitability. In this mini-review, we highlight findings from our laboratory in which we used a mammalian heterologous expression system to address mechanisms of GIRK channel regulation by Galpha and Gbetagamma subunits. We found that, like beta1- and beta2-containing Gbetagamma dimers, GIRK channels are also activated by G protein betagamma dimers containing beta3 and beta4 subunits. By contrast, GIRK currents are inhibited by beta5-containing Gbetagamma dimers and/or by Galpha proteins of the Galphaq/11 family. The properties of Gbeta5-mediated inhibition suggest that beta5-containing Gbetagamma dimers act as competitive antagonists of other activating Gbetagamma pairs on GIRK channels. Inhibition of GIRK channels by Galpha subunits is specific to members of the Galphaq/11 family and appears to result, at least in part, from activation of phospholipase C (PLC) and the resultant decrease in membrane levels of phosphatidylinositol-4,5-bisphosphate (PIP2), an endogenous co-factor necessary for GIRK channel activity; this Galphaq/11 activated mechanism is largely responsible for receptor-mediated GIRK channel inhibition.

Publication types

  • Comparative Study
  • Review

MeSH terms

  • Binding, Competitive
  • Cell Line
  • Dimerization
  • Enzyme Activation
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Heterotrimeric GTP-Binding Proteins / chemistry
  • Heterotrimeric GTP-Binding Proteins / physiology*
  • Humans
  • Ion Channel Gating
  • Ion Transport
  • Kidney
  • Membrane Potentials
  • Phosphatidylinositol 4,5-Diphosphate / physiology
  • Phosphatidylinositol Diacylglycerol-Lyase
  • Potassium / metabolism
  • Potassium Channels / chemistry
  • Potassium Channels / physiology*
  • Potassium Channels, Inwardly Rectifying*
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / physiology
  • Transfection
  • Type C Phospholipases / metabolism


  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Phosphatidylinositol 4,5-Diphosphate
  • Potassium Channels
  • Potassium Channels, Inwardly Rectifying
  • Recombinant Fusion Proteins
  • Type C Phospholipases
  • Heterotrimeric GTP-Binding Proteins
  • Phosphatidylinositol Diacylglycerol-Lyase
  • Potassium