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J. Biol. Chem., Vol. 282, Issue 16, 12154-12163, April 20, 2007

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Common Structural Requirements for Heptahelical Domain Function in Class A and Class C G Protein-coupled Receptors^*

Virginie Binet, Béatrice Duthey, Jennifer Lecaillon, Claire Vol, Julie Quoyer, Gilles Labesse^¶, Jean-Philippe Pin, and Laurent Prézeau¹

From the Département de Pharmacologie Moléculaire, Institut de Génomique Fonctionnelle, CNRS-UMR 5203, INSERM U661, Universités Montpellier 1 et 2, 34094 Montpellier Cedex 5, Centre Hospitalo-Universitaire de Montpellier, 34000 Montpellier, and ^¶Centre de Biochimie Structurale, CNRS UMR 5048, INSERM U554, Universités Montpellier 1 et 2, 34000 Montpellier, France

G protein-coupled receptors (GPCRs) are key players in cell communication. Several classes of such receptors have been identified. Although all GPCRs possess a heptahelical domain directly activating G proteins, important structural and sequence differences within receptors from different classes suggested distinct activation mechanisms. Here we show that highly conserved charged residues likely involved in an interaction network between transmembrane domains (TM) 3 and 6 at the cytoplasmic side of class C GPCRs are critical for activation of the -aminobutyric acid type B receptor. Indeed, the loss of function resulting from the mutation of the conserved lysine residue into aspartate or glutamate in the TM3 of -aminobutyric acid type B₂ can be partly rescued by mutating the conserved acidic residue of TM6 into either lysine or arginine. In addition, mutation of the conserved lysine into an acidic residue leads to a nonfunctional receptor that displays a high agonist affinity. This is reminiscent of a similar ionic network that constitutes a lock stabilizing the inactive state of many class A rhodopsin-like GPCRs. These data reveal that despite their original structure, class C GPCRs share with class A receptors at least some common structural feature controlling G protein activation.

Received for publication, December 1, 2006 , and in revised form, January 26, 2007.

^* This work was supported by grants from the CNRS, Action Concertée Incitative ACI-BCMS 328 Contract 45 491 (to J. P. P.), the French Ministry of Research Grant ANR-05-NEUR-035, the European Community EEC STREP Program GPCR from the 6th PCRDT Grant LSHB-CT-2003-503337 (to J. P. P.), and contracts with Addex Pharmaceuticals. 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.

¹ To whom correspondence should be addressed: Dépt. de Pharmacologie Moléculaire, Institut de Génomique Fonctionnelle, 141 Rue de la Cardonille, 34094 Montpellier Cedex 5, France. Tel.: 33-467-14-29-33; Fax: 33-467-54-24-32; E-mail: laurent.prezeau{at}igf.cnrs.fr.

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