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

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Bodhinathan K, Slesinger PA

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

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

PubMed ID
24145411 [ View in PubMed
]
Abstract

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 Gbetagamma 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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
EthanolG protein-activated inward rectifier potassium channel 1ProteinHumans
Unknown
Not AvailableDetails
EthanolG protein-activated inward rectifier potassium channel 2ProteinHumans
Unknown
Not AvailableDetails
EthanolG protein-activated inward rectifier potassium channel 3ProteinHumans
Unknown
Not AvailableDetails
EthanolG protein-activated inward rectifier potassium channel 4ProteinHumans
Unknown
Not AvailableDetails