A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain

Publication date: Available online 22 August 2019Source: CellAuthor(s): John V. Lin King, Joshua J. Emrick, Mark J.S. Kelly, Volker Herzig, Glenn F. King, Katalin F. Medzihradszky, David JuliusSummaryTRPA1 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.Graphical Abstract
Source: Cell - Category: Cytology Source Type: research