Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, China.
J Biol Chem. 2012 Jul 27;287(31):25905-16. doi: 10.1074/jbc.M112.364869. Epub 2012 Jun 7.
α-Hydroxyl acids (AHAs) from natural sources act as proton donors and topical compounds that penetrate skin and are well known in the cosmetic industry for their use in chemical peels and improvement of the skin. However, little is known about how AHAs cause exfoliation to expose fresh skin cells. Here we report that the transient receptor potential vanilloid 3 (TRPV3) channel in keratinocytes is potently activated by intracellular acidification induced by glycolic acid. Patch clamp recordings and cell death assay of both human keratinocyte HaCaT cells and TRPV3-expressing HEK-293 cells confirmed that intracellular acidification led to direct activation of TRPV3 and promoted cell death. Site-directed mutagenesis revealed that an N-terminal histidine residue, His-426, known to be involved in 2-aminoethyl diphenylborinate-mediated TRPV3 activation, is critical for sensing intracellular proton levels. Taken together, our findings suggest that intracellular protons can strongly activate TRPV3, and TRPV3-mediated proton sensing and cell death in keratinocytes may serve as a molecular basis for the cosmetic use of AHAs and their therapeutic potential in acidic pH-related skin disorders.
α-羟基酸（AHAs）来源于天然产物，作为质子供体和局部化合物，可以穿透皮肤，在化妆品行业中因其化学焕肤和改善皮肤的功效而广为人知。然而，AHAs 如何导致角质细胞剥落以暴露出新的皮肤细胞，目前还知之甚少。在这里，我们报告细胞内酸化诱导的瞬时受体电位香草酸 3（TRPV3）通道在角质细胞中被强烈激活。使用人角质形成细胞 HaCaT 细胞和表达 TRPV3 的 HEK-293 细胞进行膜片钳记录和细胞死亡检测，证实细胞内酸化导致 TRPV3 的直接激活，并促进细胞死亡。定点突变揭示，一个位于 N 端的组氨酸残基 His-426，已知参与 2-氨基乙基二苯硼酸盐介导的 TRPV3 激活，对于感应细胞内质子水平至关重要。综上所述，我们的研究结果表明，细胞内质子可以强烈激活 TRPV3，而 TRPV3 介导的质子感应和角质形成细胞中的细胞死亡可能是 AHAs 在化妆品中的应用及其在酸性 pH 相关皮肤疾病中的治疗潜力的分子基础。
