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J. Biol. Chem., Vol. 278, Issue 37, 35063-35070, September 12, 2003

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The Second Intracellular Loop of Metabotropic Glutamate Receptors Recognizes C Termini of G-protein -Subunits^*

Michaela Havlickova , Jaroslav Blahos , Isabelle Brabet , Jianfeng Liu , Bohdana Hruskova , Laurent Prézeau  and Jean-Philippe Pin  ¶

From the Department of Molecular Pharmacology, Institute of Experimental Medicine, Czech Academy of Science, Videnska 1083, 142 20 Prague 4, Czech Republic and the Department of Molecular Pharmacology, Laboratory for Functional Genomics, CNRS-UPR2580, 141 rue de la Cardonille, F-34094 Montpellier Cedex 5, France

Heptahelical receptor coupling selectivity to G-proteins is controlled by a large contact area that involves several portions of the receptor and each subunit of the G-protein. In the G-protein subunit, the C-terminal 5 residues, the N terminus, and the N-1 and 4–5 loops play important roles. On the receptor side, both the second and third (i2 and i3) intracellular loops as well as the C-terminal tail probably contact these different regions of the G-protein. It is now accepted that the C terminus of the subunit binds in a cavity formed by the i2 and i3 loops. Among the various G-protein-coupled receptors (GPCRs), class III receptors that include metabotropic glutamate (mGlu) receptors greatly differ from the rhodopsin-like GPCRs, but the contact zone between these receptors and the G-protein is less understood. The C terminus of the subunit has been shown to play a pivotal role in the selective recognition of class III GPCRs. Indeed, the mGlu2 and mGlu4 and -8 receptors can discriminate between subunits that differ at the level of their C-terminal end only (such as G_qo and G_qz). Here, we examine the role of the i2 loop of mGluRs in the selective recognition of this region of the subunit. To that aim, we analyzed the coupling properties of mGlu2 and mGlu4 or -8 receptors and chimeras containing the i2 loop of the converse receptor to G-protein subunits that only differ by their C termini (G_qo,G_qz, and their point mutants). Our data demonstrate that the central portion of the i2 loop is responsible for the selective recognition of the C-terminal end of the subunit, especially the residue on position –4. These data are consistent with the proposal that the C-terminal end of the G-protein subunit interacts with residues in a cavity formed by the i2 and i3 loops in class III GPCRs, as reported for class I GPCRs.

Received for publication, June 20, 2003

^* This work was supported by the CNRS (to J. P. P.), the Action Concertée Incitative "Molécules et Cibles Thérapeutiques" of the French ministry of Research and Technology (to J. P. P.), and the Comité Parkinson of the Fondation de France (to J. P. P.), the Grant Agency of Czech Republic (Grant GACR 301/00/0654 JB), the Grant Agency of Ministry of Healthcare of Czech Republic (Grants NL 6114-3/00; NF 6704-3/01); 5thFW EC (Grant QLG3-CT-2001-00929 "Epileptosome" JB), and 5th Framework of the European Community (Grant ICA1-CT-2000-70028 "MEDIPRA" JB). 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.

^¶ To whom correspondence should be addressed. Tel.: 33-467-14-2988 (office) or 33-467-14-2933 (laboratory); Fax: 33-467-54-2432; E-mail: jppin{at}ccipe.cnrs.fr.

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