Intracellular proton-mediated activation of TRPV3 channels accounts for the exfoliation effect of α-hydroxyl acids on keratinocytes.
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.
Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, China.
Xu
X
Cao
Fan
F
Yang
Jie
J
Zheng
Kewei
K
Wang
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001896:Boron Compounds / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003358:Cosmetics / Q000494:pharmacology; D006016:Glycolates / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007641:Keratolytic Agents / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary; D012867:Skin / Q000166:cytology / Q000187:drug effects; D050916:TRPV Cation Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
C538758:2-aminoethyl diphenylborinate; D001896:Boron Compounds; D003358:Cosmetics; D006016:Glycolates; D007641:Keratolytic Agents; D050916:TRPV Cation Channels; C459445:TRPV3 protein, human; C031149:glycolic acid