Activation and Inhibition of Thermosensitive TRP Channels by Voacangine, an Alkaloid Present in Voacanga africana, an African Tree

Abstract

Voacangine (1) is an alkaloid found in the root bark of Voacanga africana. Our previous work has suggested that 1 is a novel transient receptor potential vanilloid type 1 (TRPV1) antagonist. In this study, the agonist and antagonist activities of 1 were examined against thermosensitive TRP channels. Channel activity was evaluated mainly using TRP channel-expressing HEK cells and calcium imaging. Herein, it was shown that 1 acts as an antagonist for TRPV1 and TRPM8 but as an agonist for TRPA1 (EC50, 8 μM). The compound competitively blocked capsaicin binding to TRPV1 (IC50, 50 μM). Voacangine (1) competitively inhibited the binding of menthol to TRPM8 (IC50, 9 μM), but it showed noncompetitive inhibition against icilin (IC50, 7 μM). Moreover, the compound selectively abrogated chemical agonist-induced TRPM8 activation and did not affect cold-induced activation. Among these effects, the TRPM8 inhibition profile is unique and noteworthy, because to date no studies have reported a menthol competitive inhibitor of TRPM8 derived from a natural source. Furthermore, this is the first report of a stimulus-selective TRPM8 antagonist. Accordingly, 1 may contribute to the development of a novel class of stimulus-selective TRPM8 blockers.

Phytochemicals from Ruta graveolens Activate TAS2R Bitter Taste Receptors and TRP Channels Involved in Gustation and Nociception

“…Recently, the sphingoid leucettamols have been identified as potent TRPM8 inhibitors of marine origin [32]. While we were preparing this manuscript, a paper was also published reporting that the alkaloid voacangine, extracted from the roots of an African plant, is a potent TRPM8 inhibitor [33].…”

Cannabinoid Therapeutics in Parkinson’s Disease: Promise and Paradox

“…Given the numerous potent secondary metabolites in the Cannabis "entourage," the potential for noncannabinoid ligation of ion channels by native Cannabis preparations can be acknowledged. Remarkably, monoterpenes, terpenoids (e.g., camphor), and alkaloids do activate calcium entry via several TRP channel members, suggesting an overlapping signaling potential between both cannabinoid and entourage (68,69,84,93,97).…”

Activation of transient receptor potential ankyrin 1 by quercetin and its analogs

“…HEK293T cells that stably expressed the human TRPA1 or human TRPV1 (vanilloid receptor) using a tetracycline-inducible system were obtained as previously described 17) The cells were cultured until confluence at 37°C and 5% CO 2 in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, 100 units/ml penicillin, 100 μg/ml streptomycin, and 0.25 μg/ml amphotericin B. The activation of the TRP channels was evaluated using a fluo-4 fluorescence assay based on the intercellular calcium ion concentration ([Ca 2+ ] i ) as previously described.…”

“…The activation of the TRP channels was evaluated using a fluo-4 fluorescence assay based on the intercellular calcium ion concentration ([Ca 2+ ] i ) as previously described. 17) Briefly, the cells were cultured overnight in the 96-well plate with the medium containing tetracycline (1 μg/mL), which induced the expression of TRPA1 or TRPV1. The medium was replaced with the buffer containing fluo-4.…”