Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine.
Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine.
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作者：
Liu Q;Wang J;Wei X;Hu J;Ping C;Gao Y;Xie C;Wang P;Cao P;Cao Z;Yu Y;Li D;Yao J
多模式感觉通道瞬时受体电位香草素-3（TRPV 3）在表皮角质形成细胞中表达，并与慢性瘙痒、过敏和炎症相关的皮肤病有关。TRPV 3的功能获得性突变导致小鼠毛发生长障碍和人类Olmsted综合征。然而，TRPV 3是否以及如何成为治疗靶点仍有待阐明。我们在这里报告说，小鼠和人类TRPV 3通道是靶向的临床药物dyclampine，发挥有力的抑制作用。因此，在小鼠模型中，dyclobulin挽救了由功能获得性TRPV 3突变引起的细胞死亡并抑制了体内瘙痒症状。在单通道水平，dyclampine抑制TRPV 3的开放概率，但不单位电导。通过分子模拟和诱变，我们进一步发现了TRPV 3孔区中能够切换dyclampin抑制效率的关键残基。对达克罗宁-TRPV 3相互作用的功能和机制见解将有助于构思皮肤炎症的治疗方法。
The multimodal sensory channel transient receptor potential vanilloid-3 (TRPV3) is expressed in epidermal keratinocytes and implicated in chronic pruritus, allergy, and inflammation-related skin disorders. Gain-of-function mutations of TRPV3 cause hair growth disorders in mice and Olmsted syndrome in humans. Nevertheless, whether and how TRPV3 could be therapeutically targeted remains to be elucidated. We here report that mouse and human TRPV3 channel is targeted by the clinical medication dyclonine that exerts a potent inhibitory effect. Accordingly, dyclonine rescued cell death caused by gain-of-function TRPV3 mutations and suppressed pruritus symptoms in vivo in mouse model. At the single-channel level, dyclonine inhibited TRPV3 open probability but not the unitary conductance. By molecular simulations and mutagenesis, we further uncovered key residues in TRPV3 pore region that could toggle the inhibitory efficiency of dyclonine. The functional and mechanistic insights obtained on dyclonine-TRPV3 interaction will help to conceive therapeutics for skin inflammation.