title: A Potent and Site-Selective Agonist of TRPA1.
abstract: TRPA1 is a member of the transient receptor potential (TRP) cation channel family that is expressed primarily on sensory neurons. This chemosensor is activated through covalent modification of multiple cysteine residues with a wide range of reactive compounds including allyl isothiocyanate (AITC), a spicy component of wasabi. The present study reports on potent and selective agonists of TRPA1, discovered through screening 1657 electrophilic molecules. In an effort to validate the mode of action of hit molecules, we noted a new TRPA1-selective agonist, JT010 (molecule 1), which opens the TRPA1 channel by covalently and site-selectively binding to Cys621 (EC50 = 0.65 nM). The results suggest that a single modification of Cys621 is sufficient to open the TRPA1 channel. The TRPA1-selective probe described herein might be useful for further mechanistic studies of TRPA1 activation.
authors.affiliation: Graduate School of Medicine, Kyoto University , Kyoto, Kyoto 606-8501, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Takaya
authors.affiliation: Molecular Profiling Research Center for Drug Discovery, National Institute for Advanced Industrial Science and Technology , Koto-ku, Tokyo 135-0064, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mio
authors.forename: Takuya
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Kurokawa
authors.forename: Shinya
authors.initials: S
authors.lastname: Otsuka
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Motonari
authors.initials: M
authors.lastname: Uesugi
mesh_terms: D015220:Calcium Channels; D057809:HEK293 Cells; D006801:Humans; D009419:Nerve Tissue Proteins / Q000819:agonists*; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000819:agonists*
chemical_list: D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels