title: Role of G protein-coupled receptor kinases in the homologous desensitization of the human and mouse melanocortin 1 receptors.
abstract: The melanocortin 1 receptor, a G protein-coupled receptor positively coupled to adenylyl cyclase, is a key regulator of epidermal melanocyte proliferation and differentiation and a determinant of human skin phototype and skin cancer risk. Despite its potential importance for regulation of pigmentation, no information is available on homologous desensitization of this receptor. We found that the human melanocortin 1 receptor (MC1R) and its mouse ortholog (Mc1r) undergo homologous desensitization in melanoma cells. Desensitization is not dependent on protein kinase A, protein kinase C, calcium mobilization, or MAPKs, but is agonist dose-dependent. Both melanoma cells and normal melanocytes express two members of the G protein-coupled receptor kinase (GRK) family, GRK2 and GRK6. Cotransfection of the receptor and GRK2 or GRK6 genes in heterologous cells demonstrated that GRK2 and GRK6 impair agonist-dependent signaling by MC1R or Mc1r. However, GRK6, but not GRK2, was able to inhibit MC1R agonist-independent constitutive signaling. Expression of a dominant negative GRK2 mutant in melanoma cells increased their cAMP response to agonists. Agonist-stimulated cAMP production decreased in melanoma cells enriched with GRK6 after stable transfection. Therefore, GRK2 and GRK6 seem to be key regulators of melanocortin 1 receptor signaling and may be important determinants of skin pigmentation.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Murcia, Murcia 30100, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Sánchez-Más
authors.forename: Lidia A
authors.initials: LA
authors.lastname: Guillo
authors.forename: Paola
authors.initials: P
authors.lastname: Zanna
authors.forename: Celia
authors.initials: C
authors.lastname: Jiménez-Cervantes
authors.forename: José C
authors.initials: JC
authors.lastname: García-Borrón
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D054768:G-Protein-Coupled Receptor Kinases; D006801:Humans; D008544:Melanocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D044102:Receptor, Melanocortin, Type 1 / Q000819:agonists* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction; D012880:Skin Pigmentation; D014162:Transfection; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000494:pharmacology; D051552:beta-Adrenergic Receptor Kinases
chemical_list: D044102:Receptor, Melanocortin, Type 1; D043562:Receptors, G-Protein-Coupled; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6