Transient receptor potential vanilloid 3 (TRPV3) is highly expressed in skin keratinocytes where it forms Ca²⁺-permeable nonselective cation channels to regulate various cutaneous functions. TRPV3 expression is upregulated in many skin disorders. Here, we examined how TRPV3 affects keratinocyte proliferation and investigated the underlying mechanism. Topical application of TRPV3 agonist, carvacrol, increased skin thickness in wild type (WT) mice but not in TRPV3 knockout (KO) mice. Carvacrol promoted proliferation of human keratinocytes HaCaT cells at concentrations ≤ 100 μM, but at 300 μM, it decreased cell viability, suggesting a nonmonotonic proliferative effect. Suppression of TRPV3 expression abolished carvacrol-induced cell proliferation while overexpression of TRPV3 enhanced HaCaT cell proliferation. Carvacrol also stimulated Ca²⁺ influx and proliferation of primary keratinocytes prepared from WT but not TRPV3 KO mice, suggesting that carvacrol-stimulated cell proliferation was dependent on TRPV3-mediated Ca²⁺ influx. Mechanistic investigation demonstrated that carvacrol stimulated TGFα release and increased phosphorylation levels of EGFR, PI3K, and NF-κB, effects abolished by suppression of TRPV3 expression and CaMKII inhibition. Moreover, inhibition of CaMKII, EGFR, PI3K, or NF-κB diminished carvacrol-induced cell proliferation. We conclude that while strong activation of TRPV3 may cause cell death, moderate activation of TRPV3 promotes cell proliferation in keratinocytes through Ca²⁺/CaMKII→TGFα/EGFR→PI3K→NF-κB signaling.

Headlights

1. Carvacrol induces epidermal hyperplasia and keratinocyte proliferation.

2. TRPV3 mediates carvacrol-induced epidermal hyperplasia and keratinocyte proliferation.

3. TRPV3 acts through Ca²⁺/CaMKII→TGFα/EGFR→PI3K→NF-κB signaling to promote keratinocyte proliferation.

瞬时受体电位香草酸 3 (TRPV3) 在皮肤角质形成细胞中高度表达，形成 Ca ²⁺可渗透的非选择性阳离子通道来调节各种皮肤功能。 TRPV3 表达在许多皮肤病中上调。在这里，我们研究了 TRPV3 如何影响角质形成细胞增殖并研究其潜在机制。局部应用 TRPV3 激动剂香芹酚可增加野生型 (WT) 小鼠的皮肤厚度，但不会增加 TRPV3 敲除 (KO) 小鼠的皮肤厚度。浓度≤ 100 μM 的香芹酚可促进人角质形成细胞 HaCaT 细胞的增殖，但浓度为 300 μM 时，会降低细胞活力，表明具有非单调增殖作用。 TRPV3 表达的抑制消除了香芹酚诱导的细胞增殖，而 TRPV3 的过度表达则增强了 HaCaT 细胞的增殖。香芹酚还刺激从WT而非TRPV3 KO小鼠制备的原代角质形成细胞的Ca ²⁺流入和增殖，表明香芹酚刺激的细胞增殖依赖于TRPV3介导的Ca ²⁺流入。机制研究表明，香芹酚刺激 TGFα 释放并增加 EGFR、PI3K 和 NF-κB 的磷酸化水平，通过抑制 TRPV3 表达和抑制 CaMKII 可以消除这种作用。此外，抑制 CaMKII、EGFR、PI3K 或 NF-κB 可减少香芹酚诱导的细胞增殖。我们的结论是，虽然TRPV3的强烈激活可能导致细胞死亡，但TRPV3的适度激活通过Ca ²⁺ /CaMKII→TGFα/EGFR→PI3K→NF-κB信号传导促进角质形成细胞中的细胞增殖。

 车头灯

1、香芹酚诱导表皮增生和角质形成细胞增殖。

2.TRPV3介导香芹酚诱导的表皮增生和角质形成细胞增殖。

3. TRPV3通过Ca ²⁺ /CaMKII→TGFα/EGFR→PI3K→NF-κB信号传导促进角质形成细胞增殖。