Cryptochrome 1 activation inhibits melanogenesis and melanosome transport through negative regulation of cAMP/PKA/CREB signaling pathway

Frontiers in Pharmacology

Pharmacology

Rongyin Gao¹  Jinpeng Lv²  Ximei Zhang³  Kun Zou³  Duo Meng³ 

[1] Department of Pharmacy, Department of Dermatology, The first people’s Hospital of Changzhou, The third Affiliated Hospital of Soochow University, Changzhou, China;Department of Pharmacy, Department of Dermatology, The first people’s Hospital of Changzhou, The third Affiliated Hospital of Soochow University, Changzhou, China;School of Pharmacy, Changzhou University, Changzhou, China;School of Pharmacy, Changzhou University, Changzhou, China;

关键词: cryptochrome 1;    KL001;    melanogenesis;    melanosome transport;    cAMP/PKA/CREB pathway;   

DOI  :  10.3389/fphar.2023.1081030

 received in 2022-10-26, accepted in 2023-01-20,  发布年份 2023

来源: Frontiers

【 摘 要 】

Cutaneous pigmentation was recently shown to be an event regulated by clock proteins. Cryptochrome (CRY) is a key protein composing the feedback loop of circadian clock, however, the function of CRY in melanocytes remains unclear. Here, we found that KL001, a synthetic small molecule modulator of CRY1, inhibited melanin synthesis, as well as reduced melanocyte dendrite elongation and melanosome transport. In addition, the dominant role of CRY1 in KL001-induced anti-melanogenesis was revealed by small interfering RNA transfection. Cellular tyrosinase activity and expression level of melanogenic proteins, including tyrosinase, TRP-1, TRP-2, and transport proteins like Rab27a, Cdc42 and Myosin Va induced by α-MSH were remarkably reversed after KL001 treatment. Mechanistically, CRY1 activation inhibited melanogenesis through CREB-dependent downregulation of MITF and CREB phosphorylation was mediated by classical cAMP/PKA pathway. In addition, the other CRY1 activator, KL044 also suppressed cAMP/PKA/CREB pathway and inhibited melanogenesis. Finally, anti-melanogenic efficacy of KL001 was confirmed by determination of melanin contents in UVB-tanning model of brown guinea pigs, which indicated that targeting CRY1 activity, via topical application of small molecule activator, can be utilized therapeutically to manage human pigmentary disorders.

【 授权许可】

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Copyright © 2023 Gao, Zhang, Zou, Meng and Lv.