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.
John V Lin King  1 ,  Joshua J Emrick  2 ,  Mark J S Kelly  3 ,  Volker Herzig  4 ,  Glenn F King  4 ,  Katalin F Medzihradszky  3 ,  David Julius  5
Affiliations
  • 1. 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.
  • 2. 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.
  • 3. Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 4. Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia.
  • 5. Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].
PMID: 31447178 DOI: 10.1016/j.cell.2019.07.014
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 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.
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