Ethanol action through the BK potassium channel

这些研究的长期目标是从分子上表征体内乙醇的重要靶标在神经系统中的作用，这些靶标有助于醉酒和成瘾。线虫的正向遗传筛选已经确定了醉酒所需的几个关键的体内乙醇靶标。最引人注目的是，在C.E/Egans中，急性酒精应用的大部分醉人效应似乎是通过名为SLO-1的人类大电导钾(BK)通道的同源基因介导的。电生理分析发现，乙醇在体内增强了BK通道的活性。乙醇引起的通过BK通道的钾外流增加将导致神经元兴奋性的降低，这可能解释了乙醇对行为的大部分抑制效应。通过将C.E/Egans强大的遗传和分子技术与膜片钳记录相结合，将研究乙醇如何在体内通过BK通道产生中毒的精确机制。这项工作将试图阐明乙醇在BK通道上的作用部位 该通道的定点和随机突变。研究对乙醇异常敏感的突变体也可能识别与BK通道途径相互作用产生中毒的蛋白质。乙醇通过BK通道作用的基本分子机制的确定可能为设计治疗酒精有害影响的定向方法提供基础。

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.