Article abstract
Nature Neuroscience 12, 988 - 995 (2009)
Published online: 28 June 2009 | doi:10.1038/nn.2358
A discrete alcohol pocket involved in GIRK channel activation
Prafulla Aryal1,2, Hay Dvir3, Senyon Choe2,3 & Paul A Slesinger1,2
Abstract
Ethanol modifies neural activity in the brain by modulating ion channels. Ethanol activates G protein–gated inwardly rectifying K+ channels, but the molecular mechanism is not well understood. Here, we used a crystal structure of a mouse inward rectifier containing a bound alcohol and structure-based mutagenesis to probe a putative alcohol-binding pocket located in the cytoplasmic domains of GIRK channels. Substitutions with bulkier side-chains in the alcohol-binding pocket reduced or eliminated activation by alcohols. By contrast, alcohols inhibited constitutively open channels, such as IRK1 or GIRK2 engineered to strongly bind PIP2. Mutations in the hydrophobic alcohol-binding pocket of these channels had no effect on alcohol-dependent inhibition, suggesting an alternate site is involved in inhibition. Comparison of high-resolution structures of inwardly rectifying K+ channels suggests a model for activation of GIRK channels using this hydrophobic alcohol-binding pocket. These results provide a tool for developing therapeutic compounds that could mitigate the effects of alcohol.
- Peptide Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.
- Graduate Program in Biology, Division of Biology, University of California, San Diego, La Jolla, California, USA.
- Structural Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.
Correspondence to: Paul A Slesinger1,2 e-mail: slesinger@salk.edu
Correspondence to: Senyon Choe2,3 e-mail: choe@salk.edu
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