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J. Biol. Chem., Vol. 282, Issue 45, 33000-33008, November 9, 2007

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Activation of a Dimeric Metabotropic Glutamate Receptor by Intersubunit Rearrangement^*

From the University of Montpellier 1 and 2, CNRS UMR5203, Institute of Functional Genomics, Montpellier F-34094, France and INSERM, U661, Montpellier F-34094, France

Although many G protein-coupled receptors (GPCRs) can form dimers, a possible role of this phenomenon in their activation remains elusive. A recent and exciting proposal is that a dynamic intersubunit interplay may contribute to GPCR activation. Here, we examined this possibility using dimeric metabotropic glutamate receptors (mGluRs). We first developed a system to perfectly control their subunit composition and show that mGluR dimers do not form larger oligomers. We then examined an mGluR dimer containing one subunit in which the extracellular agonist-binding domain was uncoupled from the G protein-activating transmembrane domain. Despite this uncoupling in one protomer, agonist stimulation resulted in symmetric activation of either transmembrane domain in the dimer with the same efficiency. This, plus other data, can only be explained by an intersubunit rearrangement as the activation mechanism. Although well established for other types of receptors such as tyrosine kinase and guanylate cyclase receptors, this is the first clear demonstration that such a mechanism may also apply to GPCRs.

Received for publication, March 23, 2007 , and in revised form, July 27, 2007.

^* This work was supported in part by CNRS; INSERM; the Ministère de l'Éducation Nationale; the Ministère de l'Enseignement Supérieur et de la Recherche; Grant ACI-BCMS328 from the program "Actions Concertées Incitatives"; Grants ANR-05-PRIB-02502, ANR-BLAN06–3-135092, and ANR-05-NEUR-0121-04 from the Agence Nationale de la Recherche; a grant from the Fondation de France Comité Parkinson; and Grants STREP-GPCR and LSHB-CT-2003-503337 from the Sixth Framework Program of the European Community. 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 Figs. A–D.

¹ Supported by a grant from the Fondation Recherche Médicale.

² To whom correspondence should be addressed: Inst. de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094 Montpellier, France. Tel.: 33-4-6714-2988; Fax: 33-4-6754-2432; E-mail: jppin{at}igf.cnrs.fr.

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