Ethanol action through the BK potassium channel

这些研究的长期目标是从分子上表征乙醇在神经系统中重要体内靶点的作用，这些靶点有助于中毒和成瘾。在C.秀丽线虫已经鉴定了几种中毒所需的乙醇的关键体内靶点。最引人注目的是，大多数急性乙醇应用在C。e/egans似乎通过称为SLO-1的人类大电导钾（BK）通道的直系同源物介导。电生理学分析发现，乙醇在体内增强BK通道的活性。乙醇诱导的钾离子通过BK通道流出的增加会导致神经元兴奋性的降低，这可以解释乙醇对行为的抑制作用。通过结合C.结合膜片钳记录技术，将研究乙醇如何通过BK通道在体内产生中毒的确切机制。这项工作将试图阐明乙醇对BK通道的作用位点， 通道的定点和随机诱变。研究对乙醇异常敏感的突变体也可以识别与BK通道途径相互作用产生中毒的蛋白质。通过BK通道确定乙醇作用的基本分子机制可能为设计治疗剂以治疗酒精的有害影响提供指导方法的基础。

The long-term goal of these studies is to molecularly characterize the action of important in vivo targets of ethanol in the nervous system that contribute to intoxication and addiction. Forward genetic screens in C. elegans have identified several key in vivo targets of ethanol that are required for intoxication. Most strikingly, the majority of the intoxicating effects of acute ethanol application in C. e/egans appear to be mediated via the ortholog of the human large-conductance potassium (BK) channel called SLO-1. Electrophysiological analyses found that ethanol potentiates the activity of the BK channel in vivo. The ethanol-induced increase in potassium efflux through the BK channel would cause a decrease in neuronal excitability, which may explain much of the depressive effects of ethanol on behavior. By combining the powerful genetic and molecular techniques of C. e/egans together with patch-clamp recording, the precise mechanism for how ethanol produces intoxication via the BK channel in vivo will be examined. This work will attempt to elucidate the site of ethanol action on the BK channel through site-directed and random mutagenesis of the channel. Studying mutants that are abnormally sensitive to ethanol may also identify proteins that interact with the BK-channel pathway to produce intoxication. Determination of the fundamental molecular mechanisms of ethanol action through the BK channel may provide a basis for a directed approach to design therapeutics to treat the detrimental effects of alcohol.