A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1.
A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1.
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DOI：
10.1038/ncomms9297
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发表时间：
2015-09-30
影响因子：
16.6
通讯作者：
Lai R
中科院分区：
文献类型：
--
作者：
Yang S;Yang F;Wei N;Hong J;Li B;Luo L;Rong M;Yarov-Yarovoy V;Zheng J;Wang K;Lai R
辣椒素受体TRPV 1离子通道是一种多模式伤害感受器，通过未知的机制对热敏感。在这里，我们报告了一种新的毒素，RhTx，从中国红头蜈蚣的毒液，有效地激活TRPV 1产生剧烈的疼痛。RhTx是一种27个氨基酸的小肽，形成一个紧凑的极化分子，具有非常快速的结合动力学和对TRPV 1的高亲和力。我们表明，RhTx的目标通道的热激活机制，在体温下引起强大的热激活。RhTx-TRPV 1相互作用由毒素的高电荷C末端介导，其与通道的富含电荷的外孔区域紧密相关，在那里它可以直接与孔螺旋和转塔相互作用。这些发现表明，RhTx结合到外孔可以诱导TRPV 1热激活，因此提供了关于热激活机制的关键新结构信息。中国红头蜈蚣的毒液会引起极度的疼痛。在这里，Yang等人从蜈蚣毒液中鉴定出一种新的毒素蛋白，并发现它可以通过与通道的外孔结合来激活伤害性TRPV 1离子通道，从而增强热激活机制。
The capsaicin receptor TRPV1 ion channel is a polymodal nociceptor that responds to heat with exquisite sensitivity through an unknown mechanism. Here we report the identification of a novel toxin, RhTx, from the venom of the Chinese red-headed centipede that potently activates TRPV1 to produce excruciating pain. RhTx is a 27-amino-acid small peptide that forms a compact polarized molecule with very rapid binding kinetics and high affinity for TRPV1. We show that RhTx targets the channel's heat activation machinery to cause powerful heat activation at body temperature. The RhTx–TRPV1 interaction is mediated by the toxin's highly charged C terminus, which associates tightly to the charge-rich outer pore region of the channel where it can directly interact with the pore helix and turret. These findings demonstrate that RhTx binding to the outer pore can induce TRPV1 heat activation, therefore providing crucial new structural information on the heat activation machinery. The venom of the Chinese red-headed centipede causes excruciating pain. Here, Yang et al. identify a novel toxin protein from the centipede venom and find that it can activate the nociceptive TRPV1 ion channel by binding to the channel's outer pore to potentiate the heat activation machinery.