Journal article
A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain
Cell, Vol.178(6), pp.1362-1374.e16
2019
Abstract
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 StatesJ J Emrick (Author) - University of California, United StatesM J S Kelly (Author) - University of California, United StatesVolker Herzig (Author) - University of QueenslandG F King (Author) - University of QueenslandK F Medzihradszky (Author) - University of California, United StatesD Julius (Author) - University of California, United States
- Publication details
- Cell, Vol.178(6), pp.1362-1374.e16
- Publisher
- Cell Press
- DOI
- 10.1016/j.cell.2019.07.014
- ISSN
- 0092-8674
- Organisation Unit
- School of Science and Engineering - Legacy; School of Science, Technology and Engineering; University of the Sunshine Coast, Queensland; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 99450829502621
- Output Type
- Journal article
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- Domestic collaboration
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- Biochemistry & Molecular Biology
- Cell Biology
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