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J. Biol. Chem., Vol. 281, Issue 49, 37447-37456, December 8, 2006

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The Natural Inverse Agonist Agouti-related Protein Induces Arrestin-mediated Endocytosis of Melanocortin-3 and -4 Receptors^*

Andreas Breit, Katharina Wolff, Hermann Kalwa, Hubertus Jarry, Thomas Büch, and Thomas Gudermann¹

From the Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, 35033 Marburg, Germany and Zentrum für Frauenheilkunde, Abteilung für Klinische und Experimentelle Endokrinologie, Universität Göttingen, 37075 Göttingen, Germany

Agouti-related protein (Agrp), one of the two naturally occurring inverse agonists known to inhibit G protein-coupled receptor activity, regulates energy expenditure by decreasing basal and blocking agonist-promoted melanocortin receptor (MCR) signaling. Here we report that, in addition to its inverse agonistic activities, Agrp exhibits agonistic properties on the endocytosis pathway of melanocortin receptors. Sustained exposure of human embryonic kidney 293 cells to Agrp induced endocytosis of the MC3R or the MC4R. The extent and kinetics of Agrp-promoted MCR endocytosis were similar to the endocytosis induced by melanocortins. Using the bioluminescence resonance energy transfer technique, we further showed that after binding of Agrp both MCRs interacted with -arrestins. In line with this observation, in COS-7 cells co-expression of -arrestins enhanced Agrp-induced MCR endocytosis, whereas in human embryonic kidney 293 cells co-transfection of -arrestin-specific small interference RNAs diminished Agrp-promoted endocytosis. This new regulatory mechanism was likewise detectable in a cell line derived from murine hypothalamic neurons endogenously expressing MC4R, pointing to the physiological relevance of Agrp-promoted receptor endocytosis. In conclusion, we demonstrated that Agrp does not solely act by directly blocking MCR signaling but also by reducing the amount of MCR molecules accessible to melanocortins at the cell surface. This -arrestin-dependent mechanism reveals a new aspect of MCR signaling in particular and refines the concept of G protein-coupled receptor antagonism in general.

Received for publication, June 22, 2006 , and in revised form, October 12, 2006.

^* This study was supported by the "Bundesministerium für Bildung und Forschung" as a part of the NGFN-2 (Nationales Genomforschungsnetzwerk: N2NV-S30T09) network. 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. Tel.: 49-6421-286-5000; Fax: 49-6421-286-5600; E-mail: guderman{at}staff.uni-marburg.de.

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