Genetic gain-of-function mutations of warm temperature-sensitive transient receptor potential vanilloid 3 (TRPV3) channel cause Olmsted syndrome characterized by severe itching and keratoderma, indicating that pharmacological inhibition of TRPV3 may hold promise for therapy of chronic pruritus and skin diseases. However, currently available TRPV3 tool inhibitors are either nonselective or less potent, thus impeding the validation of TRPV3 as therapeutic target. Using whole-cell patch-clamp and single-channel recordings, we report the identification of two natural dicaffeoylquinic acid isomers isochlorogenic acid A (IAA) and isochlorogenic acid B (IAB) that selectively inhibit TRPV3 currents with IC₅₀ values of 2.7 ± 1.3 and 0.9 ± 0.3 μmol/L, respectively, and reduce the channel open probability to 3.7 ± 1.2% and 3.2 ± 1.1% from 26.9 ± 5.5%, respectively. In vivo evaluation confirms that both IAA and IAB significantly reverse the ear swelling of dermatitis and chronic pruritus. Furthermore, the isomer IAB is able to rescue the keratinocyte death induced by TRPV3 agonist carvacrol. Molecular docking combined with site-directed mutations reveals two residues T636 and F666 critical for the binding of the two isomers. Taken together, our identification of isochlorogenic acids A and B that act as specific TRPV3 channel inhibitors and gating modifiers not only provides an essential pharmacological tool for further investigation of the channel pharmacology and pathology, but also holds developmental potential for treatment of dermatitis and chronic pruritus.

温敏瞬时受体电位香草醛 3 (TRPV3) 通道的基因功能获得性突变导致以严重瘙痒和角化病为特征的奥姆斯特德综合征，表明 TRPV3 的药理学抑制可能有望治疗慢性瘙痒和皮肤病。然而，目前可用的 TRPV3 工具抑制剂要么是非选择性的，要么是效力较低的，因此阻碍了 TRPV3 作为治疗靶点的验证。使用全细胞膜片钳和单通道记录，我们报告了两种天然二咖啡酰奎宁酸异构体异绿原酸 A (IAA) 和异绿原酸 B (IAB) 的鉴定，它们通过 IC _{50选择性抑制 TRPV3 电流}值分别为 2.7 ± 1.3 和 0.9 ± 0.3 μmol/L，将通道打开概率分别从 26.9 ± 5.5% 降低到 3.7 ± 1.2% 和 3.2 ± 1.1%。体内评估证实，IAA 和 IAB 均能显着逆转皮炎和慢性瘙痒的耳肿胀。此外，异构体 IAB 能够挽救由 TRPV3 激动剂香芹酚诱导的角质形成细胞死亡。分子对接结合定点突变揭示了两个对两种异构体结合至关重要的残基 T636 和 F666。总之，我们鉴定出作为特异性 TRPV3 通道抑制剂和门控调节剂的异绿原酸 A 和 B 不仅为进一步研究通道药理学和病理学提供了必要的药理学工具，而且还具有治疗皮炎和慢性瘙痒的发展潜力.