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

Rongyin Gao; Ximei Zhang; Kun Zou; Duo Meng; Jinpeng Lv

doi:10.3389/fphar.2023.1081030

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

Front Pharmacol. 2023 Feb 6:14:1081030. doi: 10.3389/fphar.2023.1081030. eCollection 2023.

Authors

Rongyin Gao¹, Ximei Zhang², Kun Zou², Duo Meng², Jinpeng Lv^{1

2}

Affiliations

¹ Department of Pharmacy, Department of Dermatology, The first people's Hospital of Changzhou, The third Affiliated Hospital of Soochow University, Changzhou, China.
² School of Pharmacy, Changzhou University, Changzhou, China.

Abstract

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.

Keywords: KL001; cAMP/PKA/CREB pathway; cryptochrome 1; melanogenesis; melanosome transport.

Grants and funding

This study was sponsored by the National Natural Science Foundation of China (No. 82103752), the China Postdoctoral Science Foundation (No. 2021M700544), the Natural Science Research of Jiangsu Higher Education Institutions of China (No. 20KJB310024), and the Changzhou Science and Technology Program (Grant No. CJ20210125) to JL, and the Changzhou Science and Technology Program (Grant No. CJ20219029) to RYG, and the Postgraduate Research & Practice Innovation Program of Jiangsu Province (No. SJCX22_1316) to XZ.