title: Defining MC1R regulation in human melanocytes by its agonist α-melanocortin and antagonists agouti signaling protein and β-defensin 3.
abstract: The melanocortin 1 receptor (MC1R), a G(s) protein-coupled receptor, has an important role in human pigmentation. We investigated the regulation of expression and activity of the MC1R in primary human melanocyte cultures. Human β-defensin 3 (HBD3) acted as an antagonist for MC1R, inhibiting the α-melanocortin (α-melanocyte-stimulating hormone (α-MSH))-induced increase in the activities of adenylate cyclase and tyrosinase, the rate-limiting enzyme for melanogenesis. α-Melanocortin and forskolin, which activate adenylate cyclase, and 12-O-tetradecanoylphorbol-13-acetate, which activates protein kinase C, increased, whereas exposure to UV radiation reduced, MC1R gene and membrane protein expression. Brief treatment with α-MSH resulted in MC1R desensitization, whereas continuous treatment up to 3 hours caused a steady rise in cAMP, suggesting receptor recycling. Pretreatment with agouti signaling protein or HBD3 prohibited responsiveness to α-MSH, but not forskolin, suggesting receptor desensitization by these antagonists. Melanocytes from different donors expressed different levels of the G protein-coupled receptor kinases (GRKs) 2, 3, 5, and 6, as well as β-arrestin 1. Therefore, in addition to the MC1R genotype, regulation of MC1R expression and activity is expected to affect human pigmentation and the responses to UV.
authors.affiliation: Department of Dermatology, University of Cincinnati, Cincinnati, Ohio 45267-0592, USA.
authors.forename: Viki B
authors.initials: VB
authors.lastname: Swope
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Jameson
authors.forename: Kevin L
authors.initials: KL
authors.lastname: McFarland
authors.forename: Dorothy M
authors.initials: DM
authors.lastname: Supp
authors.forename: William E
authors.initials: WE
authors.lastname: Miller
authors.forename: Dennis W
authors.initials: DW
authors.lastname: McGraw
authors.forename: Mira A
authors.initials: MA
authors.lastname: Patel
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Nix
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Millhauser
authors.forename: George F
authors.initials: GF
authors.lastname: Babcock
authors.forename: Zalfa A
authors.initials: ZA
authors.lastname: Abdel-Malek
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D054366:Agouti Signaling Protein / Q000494:pharmacology*; D019390:Arrestins / Q000096:biosynthesis; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D054768:G-Protein-Coupled Receptor Kinases / Q000096:biosynthesis; D006801:Humans; D053486:Melanocortins / Q000494:pharmacology*; D008544:Melanocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D014442:Monophenol Monooxygenase / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D044102:Receptor, Melanocortin, Type 1 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D012880:Skin Pigmentation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D014466:Ultraviolet Rays; D000521:alpha-MSH / Q000494:pharmacology*; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D023083:beta-Defensins / Q000494:pharmacology*
chemical_list: C554292:12-O-tetradecanoylphorbol-1,3-acetate; C000605253:ARRB1 protein, human; C515182:ASIP protein, human; D054366:Agouti Signaling Protein; D019390:Arrestins; C422950:DEFB103A protein, human; D053486:Melanocortins; D044102:Receptor, Melanocortin, Type 1; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D023083:beta-Defensins; D005576:Colforsin; D000521:alpha-MSH; D014442:Monophenol Monooxygenase; D011493:Protein Kinase C; D054768:G-Protein-Coupled Receptor Kinases; D000262:Adenylyl Cyclases; D013755:Tetradecanoylphorbol Acetate