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J. Biol. Chem., Vol. 281, Issue 27, 18317-18326, July 7, 2006

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The Apelin Receptor Is Coupled to G_i1 or G_i2 Protein and Is Differentially Desensitized by Apelin Fragments^*

From the Unité U589 INSERM, IFR31, BP 84225, 1 avenue Jean-Poulhès, 31432-Toulouse Cédex 4, France

The apelin receptor is a G protein-coupled receptor to which two ligand fragments, apelin-(65–77) and apelin-(42–77), can bind. To address the physiological significance of the existence of dual ligands for a single receptor, we first compared the ability of the apelin fragments to regulate intracellular effectors, to promote G protein coupling, and to desensitize the response in Chinese hamster ovary cells expressing the murine apelin receptor. We found that both apelin fragments inhibited adenylyl cyclase and increased the phosphorylation of ERK or Akt. Using stably transfected cells expressing a pertussis toxin-insensitive _i subunit, we demonstrated that each apelin fragment promoted coupling of the apelin receptor to either G_i1 or G_i2 but not to G_i3. Although preincubation with each apelin fragment induced a desensitization at the level of the three effectors, preincubation with apelin-(42–77) also increased basal effector activity. In addition, a C-terminal deletion of the apelin receptor decreased the desensitization induced by apelin-(65–77) but did not alter the desensitization pattern induced by apelin-(42–77). Finally, in umbilical endothelial cells, which we have recently shown to express the apelin receptor, the G_i1 and G_i2 subunits are also expressed, ERK and Akt phosphorylation is desensitized after preincubation with apelin-(65–77), and basal levels of Akt phosphorylation are increased after preincubation with apelin-(42–77). In summary, apelin fragments regulate the same effectors, via the preferential coupling of the apelin receptor to G_i1 or G_i2, but they promote a differential desensitization pattern that may be central to their respective physiological roles.

Received for publication, January 20, 2006 , and in revised form, May 5, 2006.

^* 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 Supported by a doctoral fellowship from the Association pour la Recherche sur le Cancer.

² To whom correspondence should be addressed. Tel.: 33-5-61-32-29-61; Fax: 33-5-61-32-21-41; E-mail: yves.audigier{at}toulouse.inserm.fr.

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