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

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

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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.

Item Type: Article
Additional Information: Funding Agency and Grant Number: 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 Funding text: We thank all members of the Julius lab for provocative discussions, especially N. Bellono for guidance and advice with patch-clamp electrophysiology and D. Leitch for guidance with interpretation of transcriptomic data. We also recognize J. Poblete and J. Braz for expert technical assistance with mouse experiments. Finally, we are grateful to L.Y. Jan, R.A. Nicoll, D. Cohn, and W.J. Tang for their critical reading of the manuscript. This work was supported by an NSF Graduate Research Fellowship (1650113 to J.V.L.K), a UCSF Chuan-Lyu Discovery Fellowship (J.V.L.K), and grants from the NIH (R37 NS065071 and R35 NS105038 to D.J. and T32 GM007449 to J.V.L.K). Additional funding was provided by the NIH (Predoctoral Fellowship DE023476 to J.J.E) and the Australian National Health & Medical Research Council (Principal Research Fellowship APP1136889 and Program Grant APP1072113 to G.F.K). NMR and MS resources were funded by the NIH (S10OD023455 and P41GM103481), the UCSF Program for Breakthrough Biomedical Research TMC grant, UCSF Research Resource Program, UCSF Chancellor Funds, and the Howard Hughes Medical Institute.
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 21 Nov 2019 20:11
Last Modified: 21 Nov 2019 20:11
URI: http://real.mtak.hu/id/eprint/103548

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