PUBLICATION
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
- Authors
- Tang, H.H., Zhang, Y.F., Yang, L.L., Hong, C., Chen, K.X., Li, Y.M., Wu, H.L.
- ID
- ZDB-PUB-230325-37
- Date
- 2023
- Source
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology 37: e22893e22893 (Journal)
- Registered Authors
- Keywords
- 5-HT7 receptor, melanogenesis, melanosome, serotonin, stress
- MeSH Terms
-
- Zebrafish/metabolism
- Cell Line, Tumor
- Mice
- rab27 GTP-Binding Proteins/metabolism
- rhoA GTP-Binding Protein/genetics
- rhoA GTP-Binding Protein/metabolism
- Animals
- Melanins
- Serotonin*/metabolism
- Serotonin*/pharmacology
- Proto-Oncogene Proteins c-akt/metabolism
- Pigmentation Disorders*/metabolism
- Pigmentation
- Melanocytes/metabolism
- Phosphatidylinositol 3-Kinases/metabolism
- Humans
- Signal Transduction
- PubMed
- 36961387 Full text @ FASEB J.
Citation
Tang, H.H., Zhang, Y.F., Yang, L.L., Hong, C., Chen, K.X., Li, Y.M., Wu, H.L. (2023) 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. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 37:e22893e22893.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping