期刊
CELL
卷 178, 期 6, 页码 1362-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2019.07.014
关键词
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资金
- NSF [1650113]
- UCSF Chuan-Lyu Discovery Fellowship
- NIH [R37 NS065071, R35 NS105038, T32 GM007449, DE023476, S10OD023455, P41GM103481]
- Australian National Health & Medical Research Council [APP1136889, APP1072113]
- UCSF Program for Breakthrough Biomedical Research TMC grant
- UCSF Research Resource Program
- UCSF Chancellor Funds
- Howard Hughes Medical Institute
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.
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