title: Endocannabinoids stimulate human melanogenesis via type-1 cannabinoid receptor.
abstract: We show that a fully functional endocannabinoid system is present in primary human melanocytes (normal human epidermal melanocyte cells), including anandamide (AEA), 2-arachidonoylglycerol, the respective target receptors (CB(1), CB(2), and TRPV1), and their metabolic enzymes. We also show that at higher concentrations AEA induces normal human epidermal melanocyte apoptosis (∼3-fold over controls at 5 μM) through a TRPV1-mediated pathway that increases DNA fragmentation and p53 expression. However, at lower concentrations, AEA and other CB(1)-binding endocannabinoids dose-dependently stimulate melanin synthesis and enhance tyrosinase gene expression and activity (∼3- and ∼2-fold over controls at 1 μM). This CB(1)-dependent activity was fully abolished by the selective CB(1) antagonist SR141716 or by RNA interference of the receptor. CB(1) signaling engaged p38 and p42/44 mitogen-activated protein kinases, which in turn activated the cyclic AMP response element-binding protein and the microphthalmia-associated transcription factor. Silencing of tyrosinase or microphthalmia-associated transcription factor further demonstrated the involvement of these proteins in AEA-induced melanogenesis. In addition, CB(1) activation did not engage the key regulator of skin pigmentation, cyclic AMP, showing a major difference compared with the regulation of melanogenesis by α-melanocyte-stimulating hormone through melanocortin 1 receptor.
authors.affiliation: Department of Biomedical Sciences, University of Teramo, 64100 Teramo, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Pucci
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pasquariello
authors.forename: Natalia
authors.initials: N
authors.lastname: Battista
authors.forename: Monia
authors.initials: M
authors.lastname: Di Tommaso
authors.forename: Cinzia
authors.initials: C
authors.lastname: Rapino
authors.forename: Filomena
authors.initials: F
authors.lastname: Fezza
authors.forename: Michela
authors.initials: M
authors.lastname: Zuccolo
authors.forename: Roland
authors.initials: R
authors.lastname: Jourdain
authors.forename: Alessandro
authors.initials: A
authors.lastname: Finazzi Agrò
authors.forename: Lionel
authors.initials: L
authors.lastname: Breton
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D015153:Blotting, Western; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D015870:Gene Expression / Q000187:drug effects; D005989:Glycerides / Q000378:metabolism / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008543:Melanins / Q000378:metabolism*; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D034622:RNA Interference; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077285:Rimonabant; D000521:alpha-MSH / Q000494:pharmacology
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D017362:Cyclic AMP Response Element-Binding Protein; D063388:Endocannabinoids; D005989:Glycerides; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000521:alpha-MSH; C094503:glyceryl 2-arachidonate; D000242:Cyclic AMP; D014442:Monophenol Monooxygenase; D020928:Mitogen-Activated Protein Kinases; D000077285:Rimonabant; C078814:anandamide