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guotieying

银虫 (正式写手)

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注册: 2008-03-05
专业: 作物种质资源与遗传育种学

[交流] Nature Neurosci.：大脑醉酒反应的分子机制

人喝醉后，通常感觉晕头转向，大脑好像不转了一样，但对于大脑为什么会出现这样的反应却不清楚。美国一项最新研究就查明了醉酒过程中大脑活动的具体分子机制。研究成人员称这将有助于开发针对酒精中毒、药物上瘾甚至癫痫症的新型疗法。

美国索尔克生物研究所科研人员在新一期《自然·神经科学》杂志上报告说，酒精成分即乙醇，被认为会改变大脑内神经细胞之间的信号传递。此前一些研究认为，乙醇会直接与离子通道蛋白质相互作用，但到目前都没有查明相互作用的具体位置。

索尔克生物研究所最新的研究发现，乙醇与大脑中一种钾离子通道蛋白质内的某个特定位置相互作用。医学研究已知，这种名为GIRK的钾离子通道在药物滥用和癫痫发作时的大脑活动中扮演关键角色。

最新的实验就发现，乙醇与蛋白质内的特定位置结合后，这一通道被激活“开启”，神经细胞之间的“通信联络”会被减弱，大脑内相当于产生了“短路”。

研究人员说，查明乙醇激活GIRK通道的具体位置，将有助于开发治疗相关大脑疾病的新疗法。比如，可以开发出一种靶向药物，使乙醇无法与通道蛋白质结合，来治疗酒精依赖。

Nature Neuroscience 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.

1 Peptide Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.
2 Graduate Program in Biology, Division of Biology, University of California, San Diego, La Jolla, California, USA.
3 Structural Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.

[ Last edited by guotieying on 2009-6-30 at 09:18 ]

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