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A Molecular Target for an Alcohol Chain-Length Cutoff

机译：醇链长度截止的分子靶标

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摘要

Despite the widespread consumption of ethanol, mechanisms underlying its anesthetic effects remain uncertain. n-Alcohols induce anesthesia up to a specific chain length and then lose potency-an observation known as the "chain-length cutoff effect." This cutoff effect is thought to be mediated by alcohol binding sites on proteins such as ion channels, but where these sites are for long-chain alcohols and how they mediate a cutoff remain poorly defined. In animals, the enzyme phospholipase D (PLD) has been shown to generate alcohol metabolites (e.g., phosphatidylethanol) with a cutoff, but no phenotype has been shown connecting PLD to an anesthetic effect. Here we show loss of PLD blocks ethanol-mediated hyperactivity in Drosophila melanogaster (fruit fly), demonstrating that PLD mediates behavioral responses to alcohol in vivo. Furthermore, the metabolite phosphatidylethanol directly competes for the endogenous PLD product phosphatidic acid at lipid-binding sites within potassium channels [e.g., TWIK-related K+ channel type 1 (K2P2.1, TREK-1)]. This gives rise to a PLD-dependent cutoff in TREK-1. We propose an alcohol pathway where PLD produces lipid-alcohol metabolites that bind to and regulate downstream effector molecules including lipid-regulated potassium channels. (C) 2018 Elsevier Ltd.
机译：尽管乙醇消耗普遍消耗，但其麻醉效应的机制仍然不确定。 N-醇诱导麻醉到特定链长，然后失去效力 - 一种称为“链长截止效应”的观察。认为这种截止效果被醇结合位点介导的蛋白质，例如离子通道，但是这些位点用于长链醇以及它们如何介导截止仍然定义差。在动物中，已显示酶磷脂酶D（PLD）以通过截止产生醇代谢物（例如，磷脂酰乙醇），但是没有将PLD连接到麻醉效果的表型。在这里，我们展示了PLD阻滞乙醇介导的果蝇（果蝇）中的乙醇介导的多动，展示了PLD在体内介导对酒精的行为反应。此外，代谢产物磷脂酰乙醇直接竞争在钾通道内的脂质结合位点的内源性PLD产物磷脂酸[例如，TWIK相关k +通道型1（K2P2.1，TREK-1）]。这引发了Trek-1中的PLD依赖性截止值。我们提出了一种醇途径，其中PLD产生脂质 - 醇代谢物，其结合并调节下游效应分子，包括血脂调节的钾通道。 （c）2018年elsevier有限公司

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