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The effect and behavior of the 5\u2010HT7 receptor (5\u2010HT7R) in melanogenesis in high vertebrates remain unknown. Herein, we examine the role and molecular mechanism of 5\u2010HT7R in the pigmentation of human skin cells, human tissue, mice, and zebrafish models. Firstly, 5\u2010HT7R protein expression decreased significantly in stress\u2010induced depigmentation skin and vitiligo epidermis. Stressed mice received transdermal serotonin 5\u2010HT7R selective agonists (LP\u201012, 0.01%) for 12 or 60\u2009days. Mice might recover from persistent stress\u2010induced depigmentation. The downregulation of tyrosinase (Tyr), microphthalmia\u2010associated transcription factor (Mitf) expression, and 5\u2010HT7R was consistently restored in stressed skin. High\u2010throughput RNA sequencing showed that structural organization (dendrite growth and migration) and associated pathways were activated in the dorsal skin of LP\u201012\u2010treated animals. 5\u2010HT7R selective agonist, LP\u201012, 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\u2010HT7R were dependent on the downstream signaling of cAMP\u2010PKA\u2010ERK1\/2, JNK MAPK, RhoA\/Rab27a, and PI3K\/AKT pathway activation. Importantly, pharmacological inhibition and genetic siRNA of 5\u2010HT7R by antagonist SB269970 partially\/completely abolished these functional properties and the related activated pathways in both NHMCs and B16F10 cells. Consistently,\n                    <jats:italic>htr7a<\/jats:italic>\n                    \/\n                    <jats:italic>7b<\/jats:italic>\n                    genetic knockdown in zebrafish could blockade melanogenic effects and abrogate 5\u2010HT\u2010induced melanin accumulation. Collectively, we have first identified that 5\u2010HT7R regulates melanogenesis, which may be a targeted therapy for pigmentation disorders, especially those worsened by stress.\n                  <\/jats:p>","DOI":"10.1096\/fj.202201352rr","type":"journal-article","created":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T10:46:23Z","timestamp":1679654783000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Serotonin\/\n                    <scp>5\u2010HT7<\/scp>\n                    receptor provides an adaptive signal to enhance pigmentation response to environmental stressors through\n                    <scp>cAMP\u2010PKA\u2010MAPK<\/scp>\n                    , Rab27a\/\n                    <scp>RhoA,<\/scp>\n                    and\n                    <scp>PI3K<\/scp>\n                    \/\n                    <scp>AKT<\/scp>\n                    signaling pathways"],"prefix":"10.1096","volume":"37","author":[{"given":"Hui\u2010hao","family":"Tang","sequence":"first","affiliation":[{"name":"Department of TCM Chemistry, School of Pharmacy Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010fan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of TCM Chemistry, School of Pharmacy Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li\u2010li","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Dermatology Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of TCM Chemistry, School of Pharmacy Shanghai University of Traditional 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