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PNAS 103 (51): 19564-19568

Copyright © 2006 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / PHARMACOLOGY

TRP channel activation by reversible covalent modification

Andrew Hinman, Huai-hu Chuang*, Diana M. Bautista, and David Julius{dagger}

Departments of Physiology and Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158

Contributed by David Julius, October 30, 2006

Received for publication October 4, 2006.

Abstract: Allyl isothiocyanate, the pungent principle of wasabi and other mustard oils, produces pain by activating TRPA1, an excitatory ion channel on sensory nerve endings. Isothiocyanates are membrane-permeable electrophiles that form adducts with thiols and primary amines, suggesting that covalent modification, rather than classical lock-and-key binding, accounts for their agonist properties. Indeed, we show that thiol reactive compounds of diverse structure activate TRPA1 in a manner that relies on covalent modification of cysteine residues within the cytoplasmic N terminus of the channel. These findings suggest an unusual paradigm whereby natural products activate a receptor through direct, reversible, and covalent protein modification.

Key Words: chemical modification • irritants • natural products • pain

Author contributions: A.H., H.-h.C., D.M.B., and D.J. designed research; A.H., H.-h.C., and D.M.B. performed research; A.H., H.-h.C., D.M.B., and D.J. analyzed data; and A.H. and D.J. wrote the paper.

*Present address: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0609598103/DC1.

{dagger}To whom correspondence should be addressed. E-mail: julius{at}cmp.ucsf.edu

© 2006 by The National Academy of Sciences of the USA

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