title: TRP channel activation by reversible covalent modification.
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.
authors.affiliation: Department of Physiology, University of California, San Francisco, CA 94158, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hinman
authors.forename: Huai-Hu
authors.initials: HH
authors.lastname: Chuang
authors.forename: Diana M
authors.initials: DM
authors.lastname: Bautista
authors.forename: David
authors.initials: D
authors.lastname: Julius
mesh_terms: D015220:Calcium Channels / Q000378:metabolism*; D002460:Cell Line; D003545:Cysteine / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000737:chemistry / Q000378:metabolism*; D008956:Models, Chemical; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D017879:Isothiocyanates; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels; C004471:allyl isothiocyanate; D003545:Cysteine