TRP channel activation by reversible covalent modification

A Hinman, H Chuang, DM Bautista… - Proceedings of the …, 2006 - National Acad Sciences
A Hinman, H Chuang, DM Bautista, D Julius
Proceedings of the National Academy of Sciences, 2006National Acad Sciences
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 …
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.
National Acad Sciences