Defining MC1R Regulation in Human Melanocytes by Its Agonist α-Melanocortin and Antagonists Agouti Signaling Protein and β-Defensin 3

The melanocortin 1 receptor (MC1R), a Gs 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-mela...

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Bibliographic Details
Published in:Journal of investigative dermatology 2012-09, Vol.132 (9), p.2255-2262
Main 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.
Format: Article
Language:English
Subjects:
12-O-Tetradecanoylphorbol-13-acetate
Adenylate cyclase
Adenylyl Cyclases - metabolism
Agouti Signaling Protein - pharmacology
alpha -Melanocyte-stimulating hormone
alpha-MSH - pharmacology
Antagonists
Arrestins - biosynthesis
beta -Arrestin
beta-Arrestin 1
beta-Arrestins
beta-Defensins - pharmacology
Cells, Cultured
Colforsin - pharmacology
Cyclic AMP
Defensins
double prime G protein-coupled receptor kinase
Enzymes
Forskolin
G-Protein-Coupled Receptor Kinases - biosynthesis
Genotypes
Humans
MC1R gene
Melanocortins - pharmacology
Melanocytes
Melanocytes - drug effects
Melanocytes - metabolism
Melanocytes - radiation effects
Membrane proteins
Monophenol monooxygenase
Monophenol Monooxygenase - metabolism
Pigmentation
Protein kinase C
Protein Kinase C - metabolism
Receptor, Melanocortin, Type 1 - agonists
Receptor, Melanocortin, Type 1 - antagonists & inhibitors
Receptor, Melanocortin, Type 1 - biosynthesis
Recycling
Skin Pigmentation - drug effects
Skin Pigmentation - physiology
Skin Pigmentation - radiation effects
Tetradecanoylphorbol Acetate - analogs & derivatives
Tetradecanoylphorbol Acetate - pharmacology
U.V. radiation
Ultraviolet Rays
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Summary:The melanocortin 1 receptor (MC1R), a Gs 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 3hours 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.
ISSN:0022-202X
1523-1747
DOI:10.1038/jid.2012.135