A discrete alcohol pocket involved in GIRK channel activation.
A discrete alcohol pocket involved in GIRK channel activation.
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DOI：
10.1038/nn.2358
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发表时间：
2009-08
影响因子：
25
通讯作者：
Slesinger, Paul A.
中科院分区：
文献类型：
--
作者：
Aryal, Prafulla;Dvir, Hay;Choe, Senyon;Slesinger, Paul A.
乙醇通过调节离子通道来改变大脑中的神经活动。乙醇激活G蛋白门控的内向纠偏K+通道，但分子机制尚不清楚。在这里，我们使用含有结合酒精的小鼠内向整流器的晶体结构和基于结构的诱变来探测位于GIRK通道细胞质域的假定的酒精结合口袋。在醇结合口袋中带有较大侧链的取代减少或消除了醇的活化。相比之下，酒精抑制了组成性开放通道，如IRK1或GIRK2，它们强烈结合PIP2。这些通道的疏水醇结合口袋的突变对酒精依赖性抑制没有影响，这表明另一个位点参与了抑制。通过对内向整流K+通道的高分辨率结构的比较，提出了一种利用疏水醇结合口袋激活GIRK通道的模型。这些结果为开发可以减轻酒精影响的治疗性化合物提供了一个工具。
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 that binds PIP2 strongly. 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 utilizing this hydrophobic alcohol-binding pocket. These results provide a tool for developing therapeutic compounds that could mitigate the effects of alcohol.
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影响因子：
25
作者：
Lewohl, JM;Wilson, WR;Harris, RA
通讯作者：
Harris, RA
影响因子：
4.8
作者：
Ivanina, T;Rishal, I;Dascal, N
通讯作者：
Dascal, N
影响因子：
3.5
作者：
Clancy, SM;Fowler, CE;Slesinger, PA
通讯作者：
Slesinger, PA
影响因子：
16
作者：
Jin, TH;Peng, LY;Logothetis, DE
通讯作者：
Logothetis, DE
影响因子：
56.9
作者：
LOVINGER, DM;WHITE, G;WEIGHT, FF
通讯作者：
WEIGHT, FF