No abstract

Serotonin (5‐HT), a neurotransmitter, is essential for normal and pathological pigmentation processing, and its receptors may be therapeutical targets. The effect and behavior of the 5‐HT7 receptor (5‐HT7R) in melanogenesis in high vertebrates remain unknown. Herein, we examine the role and molecular mechanism of 5‐HT7R in the pigmentation of human skin cells, human tissue, mice, and zebrafish models. Firstly, 5‐HT7R protein expression decreased significantly in stress‐induced depigmentation skin and vitiligo epidermis. Stressed mice received transdermal serotonin 5‐HT7R selective agonists (LP‐12, 0.01%) for 12 or 60 days. Mice might recover from persistent stress‐induced depigmentation. The downregulation of tyrosinase (Tyr), microphthalmia‐associated transcription factor (Mitf) expression, and 5‐HT7R was consistently restored in stressed skin. High‐throughput RNA sequencing showed that structural organization (dendrite growth and migration) and associated pathways were activated in the dorsal skin of LP‐12‐treated animals. 5‐HT7R selective agonist, LP‐12, had been demonstrated to enhance melanin production, dendrite growth, and chemotactic motility in B16F10 cells, normal human melanocytes (NHMCs), and zebrafish. Mechanistically, the melanogenic, dendritic, and migratory functions of 5‐HT7R were dependent on the downstream signaling of cAMP‐PKA‐ERK1/2, JNK MAPK, RhoA/Rab27a, and PI3K/AKT pathway activation. Importantly, pharmacological inhibition and genetic siRNA of 5‐HT7R by antagonist SB269970 partially/completely abolished these functional properties and the related activated pathways in both NHMCs and B16F10 cells. Consistently, htr7a/7b genetic knockdown in zebrafish could blockade melanogenic effects and abrogate 5‐HT‐induced melanin accumulation. Collectively, we have first identified that 5‐HT7R regulates melanogenesis, which may be a targeted therapy for pigmentation disorders, especially those worsened by stress.

Background: The roots of Salvia miltiorrhiza Bunge (Lamiaceae) have been often used to treat vitiligo in clinical for many years. However, the main ingredient basis of efficacy has not been known. Objectives: We investigated whether the two main constituents of S. miltiorrhiza, major hydrophobic compound tanshinone IIA (Tan IIA) and the major hydrophilic compound salvianolic acid B (Sal B), had the same melanogenic activity. Methods: To testify the potential roles of Tan IIA and Sal B in pigmentation, tyrosinase (Tyr) activity, melanin synthesis ability, and the molecular mechanisms stimulating melanin production were determined in B16F10 melanoma cells. Results: Tan IIA promoted melanogenesis and enhanced Tyr activity at its maximum concentration (10 μM), whereas that of Sal B had no effect. Furthermore, the color of cell pellets and morphological observation of B16F10 cells were visibly darkened. Regarding molecular mechanisms, Western blot results showed that Tan IIA (1, 3, and 10 μM) dose dependently increased the level of phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase MAPK, respectively. However, it decreased phosphorylation in extracellular signal-regulated protein kinase 1/2 MAPK signaling. Meanwhile, Tan IIA promoted the expression of microphthalmia-associated transcription factor and Tyr. Conclusion: Tan IIA might be a melanogenic ingredient basis of S. miltiorrhiza to increase the Tyr activity by activating the upstream MAPK signaling pathways, thereby contributing to pigmentary processing.