Inhibition of transient receptor potential vanilloid 3 channels by antimalarial hydroxychloroquine alleviates TRPV3-dependent dermatitis

• Published in: The Journal of biological chemistry 2024-10, Vol.300 (10), p.107733, Article 107733
• Main Authors: Zhang, Beilei, Xie, Bo, Xu, Wen, Wei, Dongfan, Zhang, Li, Sun, Jiayi, Shi, Yetan, Feng, Jiangfeng, Yang, Fan, Zhang, Heng, Song, Xiuzu
• Format: Article
• Language: English
• Subjects: Animals; Antimalarials - pharmacology; dermatitis; Dermatitis - drug therapy; Dermatitis - metabolism; Dermatitis - pathology; electrophysiology; HCQ; HEK293 Cells; Humans; Hydroxychloroquine - pharmacology; Male; Mice; Molecular Docking Simulation; skin inflammation; TRP channel; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; TRPV3
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1016/j.jbc.2024.107733

Transient receptor potential vanilloid 3 channel (TRPV3) is closely associated with skin inflammation, but there is a lack of effective and specific inhibitors for clinical use. In this study, we identified antimalarial hydroxychloroquine (HCQ) as a selective TRPV3 inhibitor following the prediction by network pharmacology data analysis. In whole-cell patch-clamp recordings, HCQ inhibited the current of the TRPV3 channel, with an IC50 of 51.69 ± 4.78 μM. At the single-channel level, HCQ reduced the open probability of TRPV3 and decreased single-channel conductance. Molecular docking and site-directed mutagenesis confirmed that residues in the pore domain were critical for the activity of HCQ. In vivo, HCQ effectively reduced carvacrol-induced epidermal thickening, erythema, and desquamation. Additionally, the serum immunoglobulin E and inflammatory factors such as tumor necrosis factor-α and interleukin-6 were markedly decreased in the dorsal skin tissues in the HCQ treatment group, as compared to the model group. Our results suggested the antimalarial HCQ may represent a potential alleviator for treating skin inflammation by inhibiting TRPV3 channels.