This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sánchez-Más, J. Articles by García-Borrón, J. C. Search for Related Content PubMed PubMed Citation Articles by Sánchez-Más, J. Articles by García-Borrón, J. C.

Role of G Protein-Coupled Receptor Kinases in the Homologous Desensitization of the Human and Mouse Melanocortin 1 Receptors

Department of Biochemistry and Molecular Biology (J.S.-M., C.J.-C., J.C.G.-B.), School of Medicine, University of Murcia, 30100 Murcia, Spain; Department of Physiological Sciences (L.A.G.), Institute of Biological Sciences, Federal University of Goiás, 74001-970 Goiania, Brazil; and Department of Medical Biochemistry and Medical Biology (P.Z.), School of Medicine, University of Bari, 70124 Bari, Italy

Address all correspondence and requests for reprints to: J. C. García-Borrón, Department of Biochemistry and Molecular Biology, School of Medicine, University of Murcia, Murcia 30100, Spain. E-mail: gborron{at}um.es.

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.

This article has been cited by other articles:

				B. L. Sanchez-Laorden, C. Jimenez-Cervantes, and J. C. Garcia-Borron Regulation of Human Melanocortin 1 Receptor Signaling and Trafficking by Thr-308 and Ser-316 and Its Alteration in Variant Alleles Associated with Red Hair and Skin Cancer J. Biol. Chem., February 2, 2007; 282(5): 3241 - 3251. [Abstract] [Full Text] [PDF]