BACKGROUNDOlmsted syndrome (OS) is a rare genodermatosis predominantly inherited in an autosomal dominant manner, typically arising from gain-of-function (GOF) variants in the transient receptor potential channel vanilloid 3 (TRPV3) gene.OBJECTIVEThis study aims to investigate potential mechanisms underlying OS in two cases presenting with an autosomal recessive inheritance pattern.METHODSNext-generation sequencing panel was employed to identify TRPV3 variants. TRPV3 plasmids carrying specific point variations were generated and transiently transfected into HEK293T cells. Electrophysiological patch-clamp techniques were utilized to record voltage-activated and ligand-activated currents. Celltiter-Glo luminescent assay was employed to analyze the cell viabilities.RESULTSCompound heterozygous variants, c.1563 G>C (p.W521C) and c.1376 C>T (p.S459L), as well as c.1773 G>C (p.L591F) and c.2186 G>A (p.R729Q), were identified in the two OS patients respectively. Electrophysiological analysis of ligand-induced activation of TRPV3 variants demonstrated the closest correlation with clinical manifestations. All four variants displayed GOF channel activity characterized by increased sensitivity. Notably, W521C and L591F exhibited both heightened sensitivity and lower EC50 values for the TRPV3 agonist. Co-transfection with wild-type TRPV3 plasmids significantly rescued these effects. Cells co-transfected with the corresponding compound heterozygous variants exhibited intermediate electrophysiological characteristics.CONCLUSIONSIn this study, we present two cases of OS by autosomal-recessive inheritance of TPRV3 variants. This study presents a notable observation of compound heterozygous GOF variants in TRPV3, highlighting their cumulative impact on clinical manifestations. Additionally, we advocate for the use of ligand-dependent ion channel activity assays to assess the pathogenicity of TRPV3 variants in OS.

2024-10-01·Journal of Biological Chemistry

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

Article

作者: Zhang, Beilei ; Feng, Jiangfeng ; Shi, Yetan ; Yang, Fan ; Xie, Bo ; Sun, Jiayi ; Zhang, Li ; Zhang, Heng ; Wei, Dongfan ; Song, Xiuzu ; Xu, Wen

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.

2024-07-26·Journal of Natural Products

A Diterpenoid of the Medicinal Plant Andrographis paniculata Targets Cutaneous TRPV3 Channel and Relieves Itch

Article

作者: Palikova, Yulia A. ; Andreev, Yaroslav A. ; Shmygarev, Vladimir I. ; Osmakov, Dmitry I. ; Kozlov, Sergey A. ; Mineev, Konstantin S. ; Palikov, Victor A. ; Dyachenko, Igor A. ; Korolkova, Yuliya V. ; Logashina, Yulia A. ; Belozerova, Olga A. ; Kalinovskii, Aleksandr P.

Transient receptor potential vanilloid subtype 3 (TRPV3) is an ion channel implicated in skin physiology and itch. TRPV3 inhibitors can present a novel strategy for combating debilitating itch conditions, and medicinal plants are a natural pool of such compounds. Here, we report the isolation of a TRPV3-inhibiting compound from Andrographis paniculata, a medicinal plant with anti-inflammatory properties whose bioactive components are poorly characterized in terms of molecular targets. Using ¹H and ¹³C NMR and high-resolution mass spectrometry, the compound was identified as a labdane-type diterpenoid, 14-deoxy-11,12-didehydroandrographolide (ddA). The activity of the compound was evaluated by fluorescent calcium assay and manual whole-cell patch-clamp technique. ddA inhibited human TRPV3 in stably expressing CHO and HaCaT keratinocytes, acting selectively among other TRP channels implicated in itch and inflammation and not showing toxicity to HaCaT cells. Antipruritic effects of the compound were evaluated in scratching behavior models on ICR mice. ddA suppressed itch induced by the TRPV3 activator carvacrol. Additionally, ddA potently suppressed histamine-induced itch with efficacy comparable to loratadine, a clinically used antihistamine drug. These results suggest the potential of ddA as a possible safe and efficacious alternative for antipruritic therapy.

100 项与 TRPV3 antagonists 相关的药物交易

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