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.

Pinacidil, a Katp channel opener, identified as a novel agonist for TRPA1

“…To confirm the TRPA1 agonistic activity of pinacidil by a relatively direct approach, we used the whole-cell patch clamp technique. It has been reported that TRPA1 is often desensitized in the presence of extracellular Ca 2+ [10,30]. It has even been reported that calcium ions alone can directly gate heterologously expressed TRPA1 [31,32].…”

Lowering Effects of Allyl Isothiocyanate on the Number of Lymphocyte and Its Subsets in Rats

“…3) AITC content of wasabi is known to be about 100-150 mg per 100 g. 3,4) The intake of pungent components enhances sympathetic nervous activities and energy metabolism. 1,[6][7][8][9][10] In general, transient receptor potential (TRP) cation channels are deeply related to these mechanisms. 4) Especially, TRP ankyrin 1 (TRPA1) has a central role in the pain response to endogeneous inflammatory mediators and volatile irritant, including AITC (wasabi), cinnamaldehyde (cinnamon) and allicin (garlic).…”

“…[5][6][7][8][9][10] Many studies showed that TRPA1 was expressed on the protein level in several gastrointestinal mucosa of small intestine, colon and duodenal mucosa. [6][7][8][9][10] Although pungent components have been known to enhance energy consumption, there is very little information about AITC. Recent study showed that AITC induced adrenaline secretion via activation of the sensory nerves expressing TRPA1 and adrenal sympathetic nerves in rats.…”

“…4) Especially, TRP ankyrin 1 (TRPA1) has a central role in the pain response to endogeneous inflammatory mediators and volatile irritant, including AITC (wasabi), cinnamaldehyde (cinnamon) and allicin (garlic). 2,5,10) TRPA1 is known to be activated by noxious cold (< 17 • C) and is highly expressed in sensory neurons of the dorsal root, trigeminal and nodose ganglia, and hair cells of the inner ear. [5][6][7][8][9][10] Many studies showed that TRPA1 was expressed on the protein level in several gastrointestinal mucosa of small intestine, colon and duodenal mucosa.…”

“…2,5,10) TRPA1 is known to be activated by noxious cold (< 17 • C) and is highly expressed in sensory neurons of the dorsal root, trigeminal and nodose ganglia, and hair cells of the inner ear. [5][6][7][8][9][10] Many studies showed that TRPA1 was expressed on the protein level in several gastrointestinal mucosa of small intestine, colon and duodenal mucosa. [6][7][8][9][10] Although pungent components have been known to enhance energy consumption, there is very little information about AITC.…”