Serotonin/5‐HT7 receptor provides an adaptive signal to enhance pigmentation response to environmental stressors through cAMP‐PKA‐MAPK, Rab27a/RhoA, and PI3K/AKT signaling pathways

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.

Citrulluside T, Isolated from the Citrullus lanatus Stem, Inhibits Melanogenesis in α-MSH-Induced Mouse B16F10 Cells

“…transcription of MITF [30,31]. As shown in Figure 6, citrulluside T caused a concentrationdependent decrease in the expression of β-catenin and a concentration-dependent increase in the phosphorylation of β-catenin.…”

“…As a result, β-catenin accumulates in the cytoplasm and translocates to the nucleus. Conversely, activation of β-catenin phosphorylation can interfere with its translocation to the nucleus, ultimately repressing the transcription of MITF [30,31]. As shown in Figure 6, citrulluside T caused a concentration-dependent decrease in the expression of β-catenin and a concentrationdependent increase in the phosphorylation of β-catenin.…”

The Effects of 2′-Hydroxy-3,6′-Dimethoxychalcone on Melanogenesis and Inflammation

“…The close association between the PI3K/AKT pathway and glycogen synthase kinase-3β (GSK3β) has been well-established in previous studies, highlighting the role of activated AKT in phosphorylating GSK3β at Ser 9. This phosphorylation event leads to the inactivation of GSK3β, subsequently preventing the degradation of β-catenin [ 22 , 23 ]. To explore the potential inhibitory effect of 3,6′-DMC on melanogenesis, Western blot analyses were conducted on α-MSH-stimulated B16F10 cells to investigate whether 3,6′-DMC impacts the PI3K/AKT signaling pathway.…”

“…In the MAPK pathway, the phosphorylation of extracellular-signal-regulated kinase (ERK) serves as a negative signaling event which, in turn, leads to the phosphorylation of MITF, resulting in the downregulation of melanogenesis. Conversely, the phosphorylation of p38 and c-Jun N-terminal kinase (JNK) enhances the expression of MITF, thus promoting melanogenesis [ 22 , 23 ]. With this in mind, Western blot analyses were conducted to examine the potential inhibitory effects of 3,6′-DMC on melanogenesis through the MAPK signaling pathway in α-MSH-stimulated B16F10 cells.…”

“…However, we need additional data on the effects of 3,6′-DMC on the cAMP/PKA signaling pathway, particularly by assessing the level of direct cAMP production, so that the effects of 3,6′-DMC on melanogenesis can be studied further. Previous studies have shown that multiple signaling pathways are involved in the regulation of melanin synthesis, and in particular, signaling pathways involving MAPKs, including p38 MAPK, ERK, and JNK, and PI3K/AKT, are involved in the regulation of MITF expression [ 22 , 23 ]. As shown in the results in Figure 7 , we demonstrate that 3,6′-DMC inhibits melanogenesis in B16F10 cells by increasing P-ERK and decreasing P-JNK and P-P38 levels, providing evidence that 3,6′-DMC activates melanogenesis through the MAPK signaling pathway.…”