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J. Biol. Chem., Vol. 282, Issue 7, 4963-4974, February 16, 2007

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Constitutive Traffic of Melanocortin-4 Receptor in Neuro2A Cells and Immortalized Hypothalamic Neurons^*

Sameer Mohammad, Giovanna Baldini, Susana Granell, Paola Narducci, Alberto M. Martelli^¶, and Giulia Baldini¹

From the Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, the Dipartimento di Morfologia Umana Normale, via Manzoni 16, Universita' di Trieste, I-34138 Trieste, Italy, and the ^¶Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Sezione di Anatomia, Cell Signalling Laboratory, Universita' di Bologna, via Irnerio 48, I-40126 Bologna, Italy

Melanocortin-4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that binds -melanocyte-stimulating hormone (-MSH) and has a central role in the regulation of appetite and energy expenditure. Most GPCRs are endocytosed following binding to the agonist and receptor desensitization. Other GPCRs are internalized and recycled back to the plasma membrane constitutively, in the absence of the agonist. In unstimulated neuroblastoma cells and immortalized hypothalamic neurons, epitopetagged MC4R was localized both at the plasma membrane and in an intracellular compartment. These two pools of receptors were in dynamic equilibrium, with MC4R being rapidly internalized and exocytosed. In the absence of -MSH, a fraction of cell surface MC4R localized together with transferrin receptor and to clathrin-coated pits. Constitutive MC4R internalization was impaired by expression of a dominant negative dynamin mutant. Thus, MC4R is internalized together with transferrin receptor by clathrin-dependent endocytosis. Cell exposure to-MSH reduced the amount of MC4R at the plasma membrane by blocking recycling of a fraction of internalized receptor, rather than by increasing its rate of endocytosis. The data indicate that, in neuronal cells, MC4R recycles constitutively and that -MSH modulates MC4R residency at the plasma membrane by acting at an intracellular sorting step.

Received for publication, August 30, 2006 , and in revised form, November 24, 2006.

^* This work was supported by National Institutes of Health Grant R01-DK53293, by the Arkansas Tobacco Settlement (to G. B.), by Ministero dell'Universitá e della Ricerca, Progetti di Ricerca di Interesse Nazionale 2005, Italy (to A. M. M.), and by a postdoctoral grant from the Secretaria de Estado de Universidades del Ministerio de Educacion y Ciencia, Spain (to S. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205. Tel.: 501-526-7793; Fax: 501-686-8169; E-mail: gbaldini{at}uams.edu.

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