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

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 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.

Keywords: TRP channels; TRPA1; cell-penetrating peptides; chemo-nociception; ion channel biophysics; neurogenic Inflammation; pain; peptide toxins; scorpion toxins; sensory physiology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • HEK293 Cells
  • Humans
  • Mice, Inbred C57BL
  • Rats, Sprague-Dawley
  • Scorpion Venoms / pharmacology*
  • Scorpions / metabolism
  • TRPA1 Cation Channel / metabolism*


  • Scorpion Venoms
  • TRPA1 Cation Channel
  • TRPA1 protein, human
  • Trpa1 protein, mouse
  • Trpa1 protein, rat