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This version published online on January 13, 2005
Molecular Endocrinology, doi:10.1210/me.2004-0227
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Submitted on June 3, 2004
Accepted on January 3, 2005

Role of G protein-coupled receptor kinases in the homologous desensitization of the human and mouse melanocortin 1 receptors

Jesús Sánchez-Más, Lidia A. Guillo, Paola Zanna, Celia Jiménez-Cervantes, and José C García-Borrón*

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

* To whom correspondence should be addressed. E-mail: gborron{at}um.es.

The melanocortin 1 receptor, a G protein-coupled receptor (GPCR) positively coupled to adenylyl cyclase, is a key regulator of epidermal melanocytes proliferation and differentiation and a determinant of human skin phototype and skin cancer risk. In spite of 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 orthologue (Mc1r) undergo homologous desensitization in melanoma cells. Desensitization is not dependent on PKA, PKC, calcium mobilization, or MAPKs, but is agonist dose-dependent. Both melanoma cells and normal melanocytes express two members of the GPCR 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 key regulators of melanocortin 1 receptor signaling and may be important determinants of skin pigmentation.
Key words: melanocortin 1 receptor • melanocortins • desensitization • G protein-coupled receptor kinase • constitutive activity • melanoma




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