2. Academic Validation
  3. Transient Receptor Potential channels, TRPV1 and TRPA1 in melanocytes synergize UV-dependent and UV-independent melanogenesis

Transient Receptor Potential channels, TRPV1 and TRPA1 in melanocytes synergize UV-dependent and UV-independent melanogenesis

  • Br J Pharmacol. 2021 Dec;178(23):4646-4662. doi: 10.1111/bph.15643.
Qi Jia 1 2,  Weifeng Tian 3 4,  Binbin Li 5,  Wen Chen 1,  Wenjie Zhang 1,  Yang Xie 6,  Na Cheng 7,  Qi Chen 8,  Jianru Xiao 2,  Yiwang Zhang 7,  Jian Yang 9,  Shu Wang 1
Affiliations

Affiliations

  • 1 Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
  • 2 Department of Orthopedic Oncology, Changzheng Hospital, Navy Medical University, Shanghai, China.
  • 3 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, and Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • 4 Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China.
  • 5 Department of Pathology, Changzheng Hospital, Navy Medical University, Shanghai, China.
  • 6 Department of Dermatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 7 Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 8 Department of Biostatistics, Navy Medical University, Shanghai, China.
  • 9 Department of Biological Sciences, Columbia University, New York, NY, USA.
PMID: 34363226 DOI: 10.1111/bph.15643
Abstract

Background and purpose: Melanogenesis is essential for pigmentation and deregulated melanogenesis causes pigmentary diseases. Psoralen and ultraviolet A (PUVA) therapy strongly stimulates pigmentation, but the underlying molecular mechanisms are elusive.

Experimental approach: Melanin content of cultured human melanocytes was spectrophotometrically measured. Patch-clamp recordings were made in human melanocytes or HEK 293 cells transiently expressing wild type or mutant human TRPV1 and TRPA1 channels. Endogenous expression of TRPV1 and TRPA1 in melanocytes was analysed by western blotting and was knocked down with siRNA. In vivo pigmentary responses were measured by a colorimeter in mouse ear skin. The expression of TRPV1 and TRPA1 in human pigmented lesions was examined by immunohistochemical staining.

Key results: PUVA strongly stimulated melanogenesis and PUVA-induced TRPV1 and TRPA1 channel activation in melanocytes and the resulting CA2+ influx were required for the stimulated melanogenesis both in vitro and in vivo. Agonists-induced TRPV1 and TRPA1 activation alone did not stimulate melanogenesis, but it synergized UVA or intrinsic cAMP and NO signalling pathways to stimulate UV-dependent or UV-independent melanogenesis. Moreover, the expressions of TRPV1 and TRPA1 were increased in human melanocytic lesions and inhibition of both channels decreased melanin content in melanoma cells.

Conclusion and implications: TRPV1 and TRPA1 are key molecular sensors and enhancers of extrinsic and intrinsic melanogenic signals in both physiological and pathological conditions, and activation of both channels in melanocytes contributes to PUVA therapy-induced pigmentation. Our work provides a common mechanism of melanogenic regulation and highlights TRPV1 and TRPA1 as potential therapeutic targets for pigmentary disorders.

Keywords

Ca2+; PUVA; TRP channel; melanogenesis.

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