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Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18309-14. doi: 10.1073/pnas.1311406110. Epub 2013 Oct 21.

Molecular mechanism underlying ethanol activation of G-protein-gated inwardly rectifying potassium channels.

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Peptide Biology and Structural Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA 92037.


Alcohol (ethanol) produces a wide range of pharmacological effects on the nervous system through its actions on ion channels. The molecular mechanism underlying ethanol modulation of ion channels is poorly understood. Here we used a unique method of alcohol-tagging to demonstrate that alcohol activation of a G-protein-gated inwardly rectifying potassium (GIRK or Kir3) channel is mediated by a defined alcohol pocket through changes in affinity for the membrane phospholipid signaling molecule phosphatidylinositol 4,5-bisphosphate. Surprisingly, hydrophobicity and size, but not the canonical hydroxyl, were important determinants of alcohol-dependent activation. Altering levels of G protein Gβγ subunits, conversely, did not affect alcohol-dependent activation, suggesting a fundamental distinction between receptor and alcohol gating of GIRK channels. The chemical properties of the alcohol pocket revealed here might extend to other alcohol-sensitive proteins, revealing a unique protein microdomain for targeting alcohol-selective therapeutics in the treatment of alcoholism and addiction.


Dr-VSP; Kcnj6; Kir3.2; chemical modification; mPhosducin

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