加州大学旧金山分校David Julius小组鉴定到一种可穿透细胞的蝎子毒素，其能够对TRPA1和疼痛进行模式特异性的调节。这一研究成果于2019年8月22日发表在国际学术期刊《细胞》上。
研究人员发现了一种肽能蝎毒素（WaTx），它通过穿透质膜来激活TRPA1，从而进入活性亲电剂到达的相同细胞内位点。WaTx使TRPA1稳定在生物物理上不同的活性状态，其特征在于通道开放的延长和Ca 2+渗透性的降低。因此，WaTx引发急性疼痛和疼痛超敏反应，但未能触发神经肽的传出释放和通常由有害亲电剂产生的神经源性炎症。这些发现提供了趋同进化的一个典型例子，其中化学本质上不同的动物和植物衍生的刺激物靶向相同的关键变构调节位点从而差异性调节通道活性。WaTx是一种独特的药理学探针，可用于剖析TRPA1功能及其对急性和持续性疼痛的作用。
据介绍，TRPA1是一种化学感应离子通道，可作为结构多样的亲电刺激物的前哨。通道激活通过不同寻常的机制发生，这涉及在氨基末端细胞质结构域内成簇半胱氨酸残基的共价修饰。
附：英文原文
Title: A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain
Author: John V. Lin King, Joshua J. Emrick, Mark J.S. Kelly, Volker Herzig, Glenn F. King, Katalin F. Medzihradszky, David Julius
Issue&Volume: 22 August 2019
Abstract: TRPA1 is a chemosensory ion channel that functions as a sentinel for structurally diverse electrophilic irritants. Channel activation occurs through an unusual mechanism involving covalent modification of cysteine residues clustered within an amino-terminal cytoplasmic domain. Here, we describe a peptidergic scorpion toxin (WaTx) that activates TRPA1 by penetrating the plasma membrane to access the same intracellular site modified by reactive electrophiles. WaTx stabilizes TRPA1 in a biophysically distinct active state characterized by prolonged channel openings and low Ca 2+ permeability. Consequently, WaTx elicits acute pain and pain hypersensitivity but fails to trigger efferent release of neuropeptides and neurogenic inflammation typically produced by noxious electrophiles. These findings provide a striking example of convergent evolution whereby chemically disparate animal- and plant-derived irritants target the same key allosteric regulatory site to differentially modulate channel activity. WaTx is a unique pharmacological probe for dissecting TRPA1 function and its contribution to acute and persistent pain.
DOI: https://doi.org/10.1016/j.cell.2019.07.014
Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30779-2#