Activation of TRPA1 by farnesyl thiosalicylic acid.

Abstract	The nonselective cation channel TRPA1 (ANKTM1, p120) is a potential mediator of pain, and selective pharmacological modulation of this channel may be analgesic. Although several TRPA1 activators exist, these tend to be either reactive or of low potency and/or selectivity. The aim of the present study, therefore, was to identify novel TRPA1 agonists. Using a combination of calcium fluorescent assays and whole-cell electrophysiology, we discovered several compounds that possess potent, selective TRPA1-activating activity, including several lipid compounds (farnesyl thiosalicylic acid, farnesyl thioacetic acid, 15-deoxy-Delta(12,14)-prostaglandin J(2), and 5,8,11,14-eicosatetraynoic acid), and two marketed drugs: disulfiram (Antabuse; a compound used in the treatment of alcohol abuse) and the antifungal agent chlordantoin. Farnesyl thiosalicylic acid activates the channel in excised patches and in the absence of calcium. Furthermore, using a quadruple TRPA1 mutant, we show that the mechanism of action of farnesyl thiosalicylic acid differs from that of the reactive electrophilic reagent allylisothiocyanate. As a TRPA1 agonist with a potentially novel mechanism of action, farnesyl thiosalicylic acid may be useful in the study of TRPA1 channels.
Authors	Michael Maher, Hong Ao, Tue Banke, Nadia Nasser, Nyan-Tsz Wu, J Guy Breitenbucher, Sandra R Chaplan, Alan D Wickenden
Journal	Molecular pharmacology (Mol Pharmacol) Vol. 73 Issue 4 Pg. 1225-34 (Apr 2008) ISSN: 1521-0111 [Electronic] United States
PMID	18171730 (Publication Type: Journal Article)
Chemical References	Calcium Channels Isothiocyanates Nerve Tissue Proteins Salicylates TRPA1 Cation Channel TRPA1 protein, human Transient Receptor Potential Channels farnesylthiosalicylic acid Ruthenium Red Farnesol allyl isothiocyanate Calcium
Topics	Animals CHO Cells Calcium (metabolism) Calcium Channels (metabolism) Cells, Cultured Cricetinae Cricetulus Dogs Electrophysiology Farnesol (analogs & derivatives, chemistry, pharmacology) Fluorescence Ganglia, Spinal (drug effects, metabolism) Humans Ion Channel Gating (drug effects) Isothiocyanates (pharmacology) Male Nerve Tissue Proteins (agonists, metabolism) Patch-Clamp Techniques Rats Rats, Sprague-Dawley Ruthenium Red Salicylates (chemistry, pharmacology) TRPA1 Cation Channel Transfection Transient Receptor Potential Channels (agonists, metabolism)

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