Stimulation of human TRPA1 channels by clinical concentrations of the antirheumatic drug auranofin

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 compo...

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Published in:American Journal of Physiology: Cell Physiology 2013-02, Vol.304 (4), p.C354-C361
Main Authors: Hatano, Noriyuki, Suzuki, Hiroka, Muraki, Yukiko, Muraki, Katsuhiko
Format: Article
Language:English
Subjects:
Acetanilides - pharmacology
Amino Acid Substitution
Amino acids
Antirheumatic Agents - pharmacology
Auranofin - pharmacology
Calcium Channel Agonists - pharmacology
Calcium Channels - genetics
Calcium Channels - metabolism
Calcium Signaling
Chemical compounds
Gene Expression
Gold
HEK293 Cells
Humans
Membranes
Mustard Plant
Mutagenesis, Site-Directed
Nerve Tissue Proteins - agonists
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Patch-Clamp Techniques
Pharmaceuticals
Physiology
Plant Oils
Purines - pharmacology
Transient Receptor Potential Channels - agonists
Transient Receptor Potential Channels - genetics
Transient Receptor Potential Channels - metabolism
TRPA1 Cation Channel
TRPM Cation Channels - metabolism
TRPV Cation Channels - metabolism
Tumors
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Summary: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.
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00096.2012