TRP channel activation by reversible covalent modification.
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.
Hinman
Andrew
A
Department of Physiology, University of California, San Francisco, CA 94158, USA.
Chuang
Huai-Hu
HH
Bautista
Diana M
DM
Julius
David
D
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*
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