Title: Defining MC1R regulation in human melanocytes by its agonist α-melanocortin and antagonists agouti signaling protein and β-defensin 3.
Authors: Swope, Viki B; Jameson, Joshua A; McFarland, Kevin L; Supp, Dorothy M; Miller, William E; McGraw, Dennis W; Patel, Mira A; Nix, Matthew A; Millhauser, Glenn L; Babcock, George F; Abdel-Malek, Zalfa A
Published In J Invest Dermatol, (2012 Sep)
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.
PubMed ID: 22572817
MeSH Terms: Adenylyl Cyclases/metabolism; Agouti Signaling Protein/pharmacology*; Arrestins/biosynthesis; Cells, Cultured; Colforsin/pharmacology; G-Protein-Coupled Receptor Kinases/biosynthesis; Humans; Melanocortins/pharmacology*; Melanocytes/drug effects*; Melanocytes/metabolism; Melanocytes/radiation effects; Monophenol Monooxygenase/metabolism; Protein Kinase C/metabolism; Receptor, Melanocortin, Type 1/agonists*; Receptor, Melanocortin, Type 1/antagonists & inhibitors*; Receptor, Melanocortin, Type 1/biosynthesis; Skin Pigmentation/drug effects; Skin Pigmentation/physiology; Skin Pigmentation/radiation effects; Tetradecanoylphorbol Acetate/analogs & derivatives; Tetradecanoylphorbol Acetate/pharmacology; Ultraviolet Rays; alpha-MSH/pharmacology*; beta-Arrestin 1; beta-Arrestins; beta-Defensins/pharmacology*