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J. Biol. Chem., Vol. 283, Issue 30, 21084-21092, July 25, 2008

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G Protein Activation by the Leukotriene B₄ Receptor Dimer

EVIDENCE FOR AN ABSENCE OF TRANS-ACTIVATION^*

Marjorie Damian, Sophie Mary, Aimée Martin, Jean-Philippe Pin^¶, and Jean-Louis Banères¹

From the Institut des Biomolécules Max Mousseron, CNRS UMR5247, and Institut de Génomique Fonctionnelle, CNRS UMR5203, Universités Montpellier 1 et 2, Montpellier, F-34093 France and ^¶INSERM U661, Montpellier F-34094, France

There is compelling evidence that G protein-coupled receptors exist as homo- and heterodimers, but the way these assemblies function at the molecular level remains unclear. We used here the purified leukotriene B₄ receptor BLT1 stabilized in its dimeric state to analyze how a receptor dimer activates G proteins. For this, we produced heterodimers between the wild-type BLT1 and a BLT1/ALXR chimera. The latter is no longer activated by leukotriene B₄ but is still activated by ALXR agonists. In this heterodimer, agonist binding to either one of the two protomers induced asymmetric conformational changes within the receptor dimer. Of importance, no G protein activation was observed when using a dimer where the ligand-loaded protomer was not able to trigger GDP/GTP exchange due to specific mutations in its third intracellular loop, establishing that the conformation of the agonist-free protomer is not competent for G protein activation. Taken together, these data indicate that although ligand binding to one protomer in the heterodimer is associated with cross-conformational changes, a trans-activation mechanism where the ligand-free subunit would trigger GDP/GTP exchange cannot be considered in this case for G protein activation. This observation sheds light into the way GPCR dimers, in particular heterodimers, could activate their cognate G proteins.

Received for publication, December 21, 2007 , and in revised form, April 30, 2008.

^* This work was supported by CNRS and by French Ministry of Research Grants ACI BCMS 328 and ANR BLAN06-3_135092. 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 Fig. 1.

¹ To whom correspondence should be addressed: Institut des Biomolécules Max Mousseron, Faculté de Pharmacie, 15 Av. Ch. Flahault, BP 14491, 34093 Montpellier Cedex 5, France. Tel.: 33-467-548-668; Fax: 33-467-548-625; E-mail: jean-louis.baneres{at}univ-montp1.fr.

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