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

Lin King, John V.

Emrick, Joshua J.

Kelly, Mark J.S.

Herzig, Volker

King, Glenn F.

Medzihradszky, Katalin F.

Julius, David

2019

QH3011 Biochemistry / biokémia

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.

angol

Article

PeerReviewed

info:eu-repo/semantics/article

text

http://real.mtak.hu/103548/1/LinKingCell.pdf

Lin King, John V. and Emrick, Joshua J. and Kelly, Mark J.S. and Herzig, Volker and King, Glenn F. and Medzihradszky, Katalin F. and Julius, David (2019) A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain. CELL, 178 (6). pp. 1362-1374. ISSN 0092-8674

http://real.mtak.hu/103548/

https://doi.org/10.1016/j.cell.2019.07.014

MTMT:30807717 10.1016/j.cell.2019.07.014