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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Arachidonic Acids / metabolism
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Arachidonic Acids / pharmacology
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Blotting, Western
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Cannabinoid Receptor Modulators / metabolism*
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Cannabinoid Receptor Modulators / pharmacology
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Cells, Cultured
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Cyclic AMP / metabolism
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Cyclic AMP Response Element-Binding Protein / metabolism
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Dose-Response Relationship, Drug
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Endocannabinoids*
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Gene Expression / drug effects
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Glycerides / metabolism
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Glycerides / pharmacology
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HeLa Cells
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Humans
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Male
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Melanins / metabolism*
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Melanocytes / cytology
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Melanocytes / drug effects
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Melanocytes / metabolism*
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Mice
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Microphthalmia-Associated Transcription Factor / metabolism
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Mitogen-Activated Protein Kinases / metabolism
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Models, Biological
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Monophenol Monooxygenase / genetics
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Monophenol Monooxygenase / metabolism*
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Piperidines / pharmacology
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Polyunsaturated Alkamides / metabolism
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Polyunsaturated Alkamides / pharmacology
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Pyrazoles / pharmacology
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RNA Interference
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Receptor, Cannabinoid, CB1 / antagonists & inhibitors
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Receptor, Cannabinoid, CB1 / genetics
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Receptor, Cannabinoid, CB1 / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Rimonabant
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alpha-MSH / pharmacology
Substances
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Arachidonic Acids
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Cannabinoid Receptor Modulators
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Cyclic AMP Response Element-Binding Protein
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Endocannabinoids
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Glycerides
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Melanins
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Microphthalmia-Associated Transcription Factor
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Piperidines
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Polyunsaturated Alkamides
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Pyrazoles
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Receptor, Cannabinoid, CB1
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alpha-MSH
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glyceryl 2-arachidonate
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Cyclic AMP
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Monophenol Monooxygenase
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Mitogen-Activated Protein Kinases
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Rimonabant
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anandamide