A plant‐derived TRPV3 inhibitor suppresses pain and itch
- 27 January 2021
- journal article
- research article
- Published by Wiley in British Journal of Pharmacology
- Vol. 178 (7), 1669-1683
- https://doi.org/10.1111/bph.15390
Abstract
Background and Purpose Itching is the most frequent pathology in dermatology which has grievous impacts on people’s mental health and social life. Transient receptor potential vanilloid 3 (TRPV3) channel is a promising target for treating pruritus. However, few specific and potent antagonists have been reported. This study was designed to identify selective TRPV3 antagonist and elucidate its anti‐pruritus pharmacology. Experimental Approach Flexstation and calcium fluorescence imaging were conducted to track the functional compounds. Whole‐cell patch clamp was used to record itch‐related ion channel currents. Homologous recombination and site‐directed mutagenesis were employed to construct TRPV3 channel chimeras and point mutations for exploring pharmacological mechanism. Mouse models were used for in vivo anti‐pruritus assay. Key Results An acridone alkaloid (citrusinine‐II) was purified and characterized from Atalantia monophylla. It directly interacts with Y564 within S4 helix of TRPV3 to selectively inhibit the channel with a half maximal inhibitory concentration (IC50) of 12.43 μM. Citrusinine‐II showed potential efficacy to attenuate both chronic and acute itch. Intradermal administration of citrusinine‐II (143 ng/skin site) nearly completely inhibited itch behaviors. It also shows significant analgesic effects. Little side effects of the compound are observed. Conclusion and Implications By acting as a specific and potent inhibitor of TRPV3 channel, citrusinine‐II shows valuable therapeutic effects in pruritus animal models and is a promising candidate drug and/or lead molecule for the development of anti‐pruritus drugs.Funding Information
- Chinese Academy of Sciences (KC Wong Education Foundation, KFJ‐STS‐SCYD‐304, XDB31000000, Youth Innovation Promotion Association, ZSTH‐034, “Light of West China” Program)
- National Natural Science Foundation of China (21761142002, 31900332, 31930015)
- Yunnan Provincial Science and Technology Department (2019‐YT‐053, 2019ZF003, 202001AT070121, 202001AW070015, 202003AD150008)
- National Science and Technology Major Project (2018YFA0801403)
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