Serotonin (5-HT) 2A Receptor Involvement in Melanin Synthesis and Transfer via Activating the PKA/CREB Signaling Pathway

Abstract

The 5-HT2A serotonin receptor (HTR2A) has been reported to be involved in the serotonin- or serotonin receptor 2A agonist-induced melanogenesis in human melanoma cells. However, the molecular mechanisms underlying HTR2A in regulating melanogenesis remain poorly understood. In this research, cultured mouse melanoma cell line B16F10, human skin, and zebrafish embryos were used to elucidate the downstream signaling of HTR2A in regulating melanogenesis and to verify the potential application of HTR2A in the treatment of pigment-associated cutaneous diseases. We demonstrated that HTR2A antagonists (AT1015 and ketanserin) attenuated the melanogenesis induction of serotonin in both mouse melanoma cells and zebrafish embryos. The agonists of HTR2A (DOI and TCB-2) increased melanin synthesis and transfer in B16F10 cells, human skin tissue, and zebrafish embryos. Furthermore, the HTR2A agonists increased the expression of proteins related to melanosome organization and melanocyte dendrites to facilitate the melanocyte migration and melanosome transport. HTR2A antagonists and genetic knockout of zebrafish htr2aa (the homologue of mammalian HTR2A gene) were also used to clarify that HTR2A mediates serotonin and DOI in regulating melanogenesis. Finally, through small scale screening of the candidate downstream pathway, we demonstrated that HTR2A mediates the melanogenesis induction of its ligands by activating the PKA/CREB signaling pathway. In this research, we further confirmed that HTR2A is a crucial protein to mediate melanocyte function. Meanwhile, this research supports that HTR2A could be designed as a drug target for the development of chemicals to treat cutaneous diseases with melanocytes or melanogenesis abnormality.

Characterization of serotonin‐5‐HTR1E signaling pathways and its role in cell survival

“…CREB is a downstream effector of both cAMP and ERK signaling pathways 35,36 and its phosphorylation is related to various physiological processes via serotonin receptors. 37 To further explore the effect of serotonin on 5-HTR1E mediated CREB phosphorylation, we treated 5-HTR1E stable or control HEK293 cells with 1 μM 5-HT in the presence and absence of forskolin. After 20 min.…”

Serotonin Receptors and Their Involvement in Melanization of Sensory Cells in Ciona intestinalis

“…It was demonstrated that 5-HT is involved in vertebrate melanogenesis and the pathway has been investigated in different model organisms and human cell cultures. For example, 5-HT induced melanin synthesis in different cell lines and zebrafish embryos via 5HT2A receptor by upregulating Tyr and its related enzymes [ 42 , 73 , 74 ]. Fluoxetine, a selective 5-HT reuptake inhibitor, stimulated melanin production in human melanocytes and in zebrafish through 5HT1A/2A and its effect was inhibited by WAY-100635 [ 42 ].…”

The mechanistic effects of acupuncture in rodent neurodegenerative disease models: a literature review

“…Serotonergic neurons are mainly distributed in brainstem raphe nuclei, from which projections are sent to wide areas of the brain ( Paquelet et al, 2022 ; Figure 2 ). A battery of canonical signaling pathways is involved in the 5-HT-mediated system, including the phosphatidylinositol 3-kinase/protein kinase B/ mammalian target of rapamycin (PI3K-Akt/mTOR) signaling pathway, extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway ( Albert and Vahid-Ansari, 2019 ), and cAMP response element-binding protein/cAMP response element-binding protein (PKA/CREB) pathway ( Yue et al, 2022 ; Lin et al, 2023 ).…”