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J. Biol. Chem., Vol. 279, Issue 34, 36013-36021, August 20, 2004

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Constitutive Endocytic Cycle of the CB1 Cannabinoid Receptor^*

Christophe Leterrier, Damien Bonnard, Damien Carrel, Jean Rossier, and Zsolt Lenkei¶

From the ESPCI-CNRS UMR 7637, Laboratoire Neurobiologie et Diversité Cellulaire, Ecole Supérieure de Physique et de Chimie Industrielles, 10 Rue Vauquelin, 75231 Paris Cedex 05, France and INSERM U288, NeuroPsychoPharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, 91 bd de l'Hôpital, 75634 Paris Cedex 13, France

The CB1 cannabinoid receptor (CB1R) displays a significant level of ligand-independent (i.e. constitutive) activity, either when heterologously expressed in nonneuronal cells or in neurons where CB1Rs are endogenous. The present study investigates the consequences of constitutive activity on the intracellular trafficking of CB1R. When transfected in HEK-293 cells, CB1R is present at the plasma membrane, but a substantial proportion (85%) of receptors is localized in intracellular vesicles. Detailed analysis of CB1-EGFP expressed in HEK-293 cells shows that the intracellular CB1R population is mostly of endocytic origin and that treatment with inverse agonist AM281 traps CB1R at the plasma membrane through a monensin-sensitive recycling pathway. Co-transfection with dominant positive or dominant negative mutants of the small GTPases Rab5 and Rab4, but not Rab11, profoundly modifies the steady-state and ligand-induced intracellular distribution of CB1R, indicating that constitutive endocytosis is Rab5-dependent, whereas constitutive recycling is mediated by Rab4. In conclusion, our results indicate that, due to its natural constitutive activity, CB1R permanently and constitutively cycles between plasma membrane and endosomes, leading to a predominantly intracellular localization at steady state.

Received for publication, April 9, 2004 , and in revised form, June 9, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s).

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains one movie.

^¶ To whom correspondence should be addressed. Tel.: 33-1-40-79-51-84; Fax: 33-1-40-79-47-57; E-mail: zsolt.lenkei{at}espci.fr.

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