title: Molecular mechanism underlying ethanol activation of G-protein-gated inwardly rectifying potassium channels.
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 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.
authors.affiliation: Peptide Biology and Structural Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Karthik
authors.initials: K
authors.lastname: Bodhinathan
authors.forename: Paul A
authors.initials: PA
authors.lastname: Slesinger
mesh_terms: D000704:Analysis of Variance; D003460:Crystallization; D000431:Ethanol / Q000494:pharmacology*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000737:chemistry* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D016296:Mutagenesis; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D000431:Ethanol
keywords: Dr-VSP; Kcnj6; Kir3.2; chemical modification; mPhosducin