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Endocannabinoids Stimulate Human Melanogenesis via Type-1 Cannabinoid Receptor

Year: 2012

Type: article

Abstract: Background: Endocannabinoids like anandamide (AEA) play a key role in skin biology.Results: At high concentrations, AEA induces apoptosis of primary human melanocytes through TRPV1 receptors, whereas at low concentrations, it stimulates melanogenesis through CB 1 receptors.Conclusion: AEA regulates cell death or melanin synthesis through different pathways.Significance: The double effect of AEA on human melanocytes might have implications beyond skin biology.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 (ϳ3-fold over controls at 5 M) 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 (ϳ3-and ϳ2-fold over controls at 1 M).This CB 1dependent 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 microphthalmiaassociated 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 ␣-melanocyte-stimulating hormone through melanocortin 1 receptor.Endocannabinoids (eCBs) 3 are endogenous fatty acid amides and monoacylglycerols whose prototypical members are N-

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m111.314880