Vanilloid site-mediated TRPV3 activation by cannabidiol and potent inhibition by 14-deoxy-11,12-didehydroandrographolide.

Kalinovskii A.; Osmakov D.; Korolkova Y.; Sobolevsky A.; Andreev Y. · Cell calcium · 2026

**Background & Methods** This review examines the molecular mechanisms of TRPV3 (transient receptor potential vanilloid 3) channel modulation by cannabidiol (CBD) and 14-deoxy-11,12-didehydroandrographolide (DDA). The study employed calcium imaging in TRPV3-expressing CHO cells and two-electrode voltage-clamp recordings in Xenopus oocytes, combined with molecular docking and site-directed mutagenesis to characterize ligand-binding interactions. **Key Findings** • CBD activates human TRPV3 with an EC50 of 12.8 µM, while DDA acts as a potent inhibitor with an IC50 of 7 nM, representing approximately 1,829-fold greater potency than CBD's activating concentration. • DDA demonstrates modality-specific inhibition: functioning as a competitive reversible antagonist for CBD activation, a negative allosteric modulator for 2-APB activation, and remaining neutral to heat-induced activation, suggesting selective targeting without disrupting physiological temperature sensitivity. • Both CBD and DDA bind to the vanilloid site within the transmembrane region of TRPV3; site-directed mutagenesis identified critical residues (A560, L557, L664) where single substitutions either disrupted CBD activation or abolished DDA inhibition, establishing the vanilloid pocket as a key regulatory domain. **Dosage & Administration** Not reported. This is a mechanistic study characterizing receptor interactions; clinical dosing regimens were not evaluated. **Safety & Adverse Effects** Not reported. The study focused on molecular pharmacology rather than safety profiling or adverse event assessment in biological systems. **Evidence Quality** This review represents moderate-quality basic science research with significant limitations. The study employed well-established in vitro methodologies (calcium imaging and electrophysiology) in heterologous expression systems rather than native tissues or animal models, limiting direct translational applicability. Findings were obtained in CHO cells and oocytes, which may not accurately reflect TRPV3 behavior in native cutaneous tissues. The molecular docking approach, while informative, requires experimental validation through crystallographic studies. No human trials were conducted, precluding assessment of clinical efficacy or safety. The identification of DDA's modality-specific inhibition is noteworthy and mechanistically sophisticated, but further investigation in physiologically relevant systems and animal models would strengthen evidence for therapeutic development. These results provide valuable mechanistic insights supporting continued investigation of TRPV3-targeting therapeutics for cutaneous pathology.

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