一种穿细胞蝎毒素可实现 TRPA1 和疼痛的模式特异性调制。
A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain.
机构信息
Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA; Oral and Craniofacial Sciences Program, School of Dentistry, University of California, San Francisco, San Francisco, CA 94143, USA.
出版信息
Cell. 2019 Sep 5;178(6):1362-1374.e16. doi: 10.1016/j.cell.2019.07.014. Epub 2019 Aug 22.
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 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.
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发挥作用。通道的激活是通过一种不寻常的机制发生的，该机制涉及聚集在细胞质氨基末端结构域内的半胱氨酸残基的共价修饰。在这里，我们描述了一种肽蝎毒素 (WaTx)，它通过穿透质膜进入由反应性亲电物修饰的相同细胞内位点来激活 TRPA1。WaTx 以一种独特的生物物理活性状态稳定 TRPA1，其特征是通道开放时间延长和 Ca 通透性降低。因此，WaTx 会引起急性疼痛和疼痛过敏，但不会引发通常由有害亲电物引起的神经肽的传出释放和神经源性炎症。这些发现提供了一个惊人的趋同进化的例子，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，以不同的方式调节通道活性。WaTx 是一种独特的药理学探针，可用于剖析 TRPA1 的功能及其对急性和持续性疼痛的贡献。
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