title: Stimulation of human TRPA1 channels by clinical concentrations of the antirheumatic drug auranofin.
abstract: Gold compounds, which were widely used to treat rheumatoid arthritis, have been recently used as experimental agents for tumor treatment. Transient receptor potential (TRP) ankyrin repeat 1 (TRPA1) is a Ca(2+)-permeable ion channel that senses acute and inflammatory pain signals. Electrophilic compounds such as mustard oil and cinnamaldehyde activate TRPA1 by interacting with TRPA1 cysteine residues. Here we investigate the effects of the gold compound auranofin (AUR) on TRPA1 channels. Intracellular Ca(2+) and whole cell patch-clamp recordings were performed on human embryonic kidney cells transiently expressed with TRPA1, TRP melastatin 8 (TRPM8), and vanilloid type TRP (TRPV1-4) channels. AUR stimulated TRPA1 in a concentration-dependent manner with a half-maximum potency of around 1.0 μM. The AUR-induced response was effectively blocked by HC030031, a TRPA1 antagonist. On the other hand, AUR failed to activate TRPM8 and TRPV1-4 channels, which are highly expressed in sensory neurons as nociceptors. The stimulatory effect on TRPA1 channels depended on the C414, C421, C621, and C633 cysteine residues and not on the inhibition of thioredoxin reductase by AUR. Moreover, AUR effectively activated TRPA1 channels expressed in human differentiated neuroblastoma cell lines. The study shows that AUR is a potent stimulator of TRPA1 channels.
authors.affiliation: Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Hatano
authors.forename: Hiroka
authors.initials: H
authors.lastname: Suzuki
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Muraki
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Muraki
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D019943:Amino Acid Substitution; D018501:Antirheumatic Agents / Q000494:pharmacology; D001310:Auranofin / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D009149:Mustard Plant; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010938:Plant Oils; D011687:Purines / Q000494:pharmacology; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D018501:Antirheumatic Agents; D002120:Calcium Channel Agonists; D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D010938:Plant Oils; D011687:Purines; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D050916:TRPV Cation Channels; D050051:Transient Receptor Potential Channels; D001310:Auranofin; C027793:mustard oil