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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Bodhinathan, Karthik Slesinger, Paul A. |
| Description | Author Affiliation: Bodhinathan K ( Peptide Biology and Structural Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA 92037.); |
| 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 Gßγ 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 45 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-11-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Ethanol Pharmacology G Protein-Coupled Inwardly-Rectifying Potassium Channels Chemistry Metabolism Models, Molecular Protein Conformation Analysis Of Variance Crystallization HEK293 Cells Mutagenesis Patch-Clamp Techniques Phosphatidylinositol 4,5-Diphosphate Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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