Molecular mechanisms mediating inhibition of G protein-coupled inwardly-rectifying K+ channels.
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.
Lei
Qiubo
Q
Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
Jones
Miller B
MB
Talley
Edmund M
EM
Garrison
James C
JC
Bayliss
Douglas A
DA
D001667:Binding, Competitive; D002460:Cell Line; D019281:Dimerization; D004789:Enzyme Activation; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D015640:Ion Channel Gating; D017136:Ion Transport; D007668:Kidney; D008564:Membrane Potentials; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000502:physiology; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011993:Recombinant Fusion Proteins; D010738:Type C Phospholipases; D020962:Heterotrimeric GTP-Binding Proteins; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D011188:Potassium