| First Author | Aryal P | Year | 2009 |
| Journal | Nat Neurosci | Volume | 12 |
| Issue | 8 | Pages | 988-95 |
| PubMed ID | 19561601 | Mgi Jnum | J:152561 |
| Mgi Id | MGI:4359126 | Doi | 10.1038/nn.2358 |
| Citation | Aryal P, et al. (2009) A discrete alcohol pocket involved in GIRK channel activation. Nat Neurosci 12(8):988-95 |
| abstractText | 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 PIP(2). 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. |
