Molecular mechanism underlying ethanol activation of G-protein-gated inwardly rectifying potassium channels.
paper
Cited
Public
Unavailable
- Authors
- Bodhinathan, Karthik; Slesinger, Paul A
- Year
- 2013
- Journal
- Proceedings of the National Academy of Sciences of the United States of America
- PMID
- 24145411
- DOI
- 10.1073/pnas.1311406110
- PMCID
- PMC3831446
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 GΞ²Ξ³ 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.
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