Elucidation of pyrethroid and DDT receptor sites in the voltage-gated sodium channel.
Elucidation of pyrethroid and DDT receptor sites in the voltage-gated sodium channel.
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DOI：
10.1016/j.neuro.2016.08.013
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发表时间：
2017-05
期刊：
影响因子：
3.4
通讯作者：
Dong K
中科院分区：
文献类型：
--
作者：
Zhorov BS;Dong K
DDT和拟除虫菊酯杀虫剂是最早被发现作用于电压门控钠通道的神经毒素之一。20世纪60年代，Narahashi教授及其同事配备了当时新的电压钳技术，提供了DDT和丙烯菊酯（第一种商业拟除虫菊酯杀虫剂）导致龙虾和鱿鱼巨大轴突中钠电流延长流动的初步证据。在接下来的几十年里，Narahashi教授的团队以及其他实验室的持续努力使人们全面了解了DDT和拟除虫菊酯对钠通道的作用机制。快进到20世纪90年代，遗传学、药理学和毒理学数据都进一步证实了电压门控钠通道是滴滴涕和拟除虫菊酯杀虫剂的主要目标。这些杀虫剂对钠通道的门控动力学的改变导致神经系统中的重复放电和/或膜去极化。这篇小型评论重点关注Narahashi教授的先驱工作的研究以及最近的突变和计算建模分析，这些分析共同阐明了难以捉摸的拟除虫菊酯受体位点以及昆虫和哺乳动物钠通道对拟除虫菊酯的不同敏感性的分子基础。
DDT and pyrethroid insecticides were among the earliest neurotoxins identified to act on voltage-gated sodium channels. In the 1960s, equipped with, at the time, new voltage-clamp techniques, Professor Narahashi and associates provided the initial evidence that DDT and allethrin (the first commercial pyrethroid insecticide) caused prolonged flow of sodium currents in lobster and squid giant axons. Over the next several decades, continued efforts by Prof. Narahashi’s group as well as other laboratories led to a comprehensive understanding of the mechanism of action of DDT and pyrethroids on sodium channels. Fast forward to the 1990s, genetic, pharmacological and toxicological data all further confirmed voltage-gated sodium channels as the primary targets of DDT and pyrethroid insecticides. Modifications of the gating kinetics of sodium channels by these insecticides result in repetitive firing and/or membrane depolarization in the nervous system. This mini-review focuses on studies from Prof. Narahashi’s pioneer work and more recent mutational and computational modeling analyses which collectively elucidated the elusive pyrethroid receptor sites as well as the molecular basis of differential sensitivities of insect and mammalian sodium channels to pyrethroids.
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