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J. Biol. Chem., Vol. 278, Issue 42, 41541-41551, October 17, 2003

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Palmitoylation of the V2 Vasopressin Receptor Carboxyl Tail Enhances -Arrestin Recruitment Leading to Efficient Receptor Endocytosis and ERK1/2 Activation^*

Pascale G. Charest  and Michel Bouvier 

From the Department of Biochemistry and Groupe de Recherche sur le Système Nerveux Autonome, Université de Montréal, Montréal, Québec H3C 3J7, Canada

A large number of G protein-coupled receptors are palmitoylated on cysteine residues located in their carboxyl tail, but the general role of this post-translational modification remains poorly understood. Here we show that preventing palmitoylation of the V2 vasopressin receptor, by site-directed mutagenesis of cysteines 341 and 342, significantly delayed and decreased both agonist-promoted receptor endocytosis and mitogen-activated protein kinase activation. Pharmacological blockade of receptor endocytosis is without effect on the vasopressin-stimulated mitogen-activated protein kinase activity, excluding the possibility that the reduced kinase activation mediated by the palmitoylation-less mutant could result from altered receptor endocytosis. In contrast, two dominant negative mutants of -arrestin which inhibit receptor endocytosis also attenuated vasopressin-stimulated mitogen-activated protein kinase activity, suggesting that the scaffolding protein, -arrestin, represents the common link among receptor palmitoylation, endocytosis, and kinase activation. Coimmunoprecipitation and bioluminescence resonance energy transfer experiments confirmed that inhibiting receptor palmitoylation considerably reduced the vasopressin-stimulated recruitment of -arrestin to the receptor. Interestingly, the changes in -arrestin recruitment kinetics were similar to those observed for vasopressin-stimulated receptor endocytosis and mitogen-activated protein kinase activation. Taken together the results indicate that palmitoylation enhances the recruitment of -arrestin to the activated V2 vasopressin receptor thus facilitating processes requiring the scaffolding action of -arrestin.

Received for publication, June 20, 2003 , and in revised form, July 21, 2003.

^* This work was supported in part by grants from the Canadian Institute for Health Research and the Québec Heart and Stroke Foundation. 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.

Supported by doctoral fellowships from the Heart and Stroke Foundation of Canada and the Fonds de Recherche en Santé du Québec.

Holder of Canada Research Chair in Signal Transduction and Molecular Pharmacology. To whom correspondence should be addressed: Dept. de Biochimie, Université de Montréal, C. P. 6128 Succursale Centre-Ville, Montréal, Québec H3C 3J7, Canada. E-mail: michel.bouvier{at}umontreal.ca.

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