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J. Biol. Chem., Vol. 280, Issue 30, 27924-27934, July 29, 2005

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Uncoupling and Endocytosis of 5-Hydroxytryptamine 4 Receptors

DISTINCT MOLECULAR EVENTS WITH DIFFERENT GRK2 REQUIREMENTS^*

Gaël Barthet, Florence Gaven, Bérénice Framery, Katsuhiro Shinjo, Takaaki Nakamura, Sylvie Claeysen, Joël Bockaert¶, and Aline Dumuis

From the CNRS UMR5203, Montpellier, F-34094 France, INSERM, U661, Montpellier, F-34094 France, Université Montpellier I, Montpellier, F-34094 France, Université Montpellier II, Montpellier, F-34094 France, Institut de Génomique Fonctionnelle, 141 Rue de la Cardonille, Montpellier F-34094 Cedex 5, France, and Nagoya Laboratories, Pfizer Japan Incorporated, 5-2 Taketoyo, Aichi 470-2393, Japan

The 5-hydroxytryptamine type 4 receptors (5-HT₄Rs) are involved in memory, cognition, feeding, respiratory control, and gastrointestinal motility through activation of a G_s/cAMP pathway. We have shown that 5-HT₄R undergoes rapid and profound homologous uncoupling in neurons. However, no significant uncoupling was observed in COS-7 or HEK293 cells, which expressed either no or a weak concentration of GRK2, respectively. High expression of GRK2 in neurons is likely to be the reason for this difference because overexpression of GRK2 in COS-7 and HEK293 cells reproduced rapid and profound uncoupling of 5-HT₄R. We have also shown, for the first time, that GRK2 requirements for uncoupling and endocytosis were very different. Indeed, -arrestin/dynamin-dependent endocytosis was observed in HEK293 cells without any need of GRK2 overexpression. In addition to this difference, uncoupling and -arrestin/dynamin-dependent endocytosis were mediated through distinct mechanisms. Neither uncoupling nor -arrestin/dynamin-dependent endocytosis required the serine and threonine residues localized within the specific C-terminal domains of the 5-HT₄R splice variants. In contrast, a cluster of serines and threonines, common to all variants, was an absolute requirement for -arrestin/dynamin-dependent receptor endocytosis, but not for receptor uncoupling. Furthermore, -arrestin/dynamin-dependent endocytosis and uncoupling were dependent on and independent of GRK2 kinase activity, respectively. These results clearly demonstrate that the uncoupling and endocytosis of 5-HT₄R require different GRK2 concentrations and involve distinct molecular events.

Received for publication, March 1, 2005 , and in revised form, May 24, 2005.

^* This work was supported by grants from CNRS, the Génopole de Montpellier, and Pfizer Japan Inc. and by Grant LSHB-CT-2003-503337 from the European Community Sixth Framework Program. 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 Supplemental Table 1.

^¶ To whom correspondence should be addressed: Dépt. de Neurobiologie, Inst. de Génomique Fonctionnelle, 141 Rue de la Cardonille, Montpellier F-34094 Cedex 5, France. Tel.: 33-4-6714-2930; Fax: 33-4-6714-2910 or 33-4-6754-2432; E-mail: joel.bockaert{at}igf.cnrs.fr.

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