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

J V Lin King; J J Emrick; M J S Kelly; Volker Herzig; G F King; K F Medzihradszky; D Julius

doi:10.1016/j.cell.2019.07.014

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

Journal article

Peer reviewed

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

J V Lin King, J J Emrick, M J S Kelly, Volker Herzig, G F King, K F Medzihradszky and D Julius

Cell, Vol.178(6), pp.1362-1374.e16

2019

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

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Abstract

Pain

TRP channels

TRPA1

ion channel biophysics

peptide toxins

sensory physiology

chemo-nociception

neurogenic inflammation

scorpion toxins

cell-penetrating peptides

A selective cell-penetrating scorpion toxin targets the irritant receptor, TRPA1, via a distinct biochemical mechanism from that used by irritants, allowing definition of a new mechanism of channel activation and interrogation of pathways of pain sensitization. © 2019 Elsevier Inc. 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.

Details

Title: A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain
Authors: J V Lin King (Author) - University of California, United States
J J Emrick (Author) - University of California, United States
M J S Kelly (Author) - University of California, United States
Volker Herzig (Author) - University of Queensland
G F King (Author) - University of Queensland
K F Medzihradszky (Author) - University of California, United States
D Julius (Author) - University of California, United States
Publication details: Cell, Vol.178(6), pp.1362-1374.e16
Publisher: Cell Press
Date published: 2019
DOI: 10.1016/j.cell.2019.07.014
ISSN: 0092-8674
Organisation Unit: School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 99450829502621
Output Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Biochemistry & Molecular Biology; Cell Biology

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