A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain
A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain
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DOI：
10.1016/j.cell.2019.07.014
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发表时间：
2019-09-05
期刊：
影响因子：
64.5
通讯作者：
Julius, David
中科院分区：
文献类型：
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作者：
King, John V. Lin;Emrick, Joshua J.;Julius, David
TRPA1是一种化学感觉离子通道，作为结构多样的亲电刺激物的哨兵。通道激活是通过一种不寻常的机制发生的，涉及聚集在氨基端细胞质域内的半胱氨酸残基的共价修饰。在这里，我们描述了一种肽能蝎子毒素（WaTx），它通过穿透质膜进入被反应性亲电试剂修饰的相同细胞内位点来激活TRPA1。WaTx使TRPA1处于生物物理上独特的活性状态，其特征是通道开放时间延长和Ca2+渗透率低。因此，WaTx引起急性疼痛和疼痛超敏反应，但不能触发神经肽的传出释放和神经源性炎症，通常由有害的亲电试剂产生。这些发现为趋同进化提供了一个引人注目的例子，即化学上不同的动物和植物来源的刺激物针对相同的关键变构调节位点来不同地调节通道活性。WaTx是一种独特的药理学探针，用于解剖TRPA1功能及其在急性和持续性疼痛中的作用。
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 Ca2+ 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.