Article
- The EMBO Journal (2005) 24, 499 - 509
- doi:10.1038/sj.emboj.7600557
Published online: 20 January 2005
Subject Category:
Evidence for a single heptahelical domain being turned on upon activation of a dimeric GPCR
Veronika Hlavackova1,2,a, Cyril Goudet2,a, Julie Kniazeff2, Alice Zikova1, Damien Maurel2,3, Claire Vol2, Johana Trojanova1, Laurent Prézeau2, Jean-Philippe Pin2,4 and Jaroslav Blahos1,4
- Department of Molecular Pharmacology, Institute of Experimental Medicine, Czech Academy of Science, Prague, Czech Republic
- Department of Molecular Pharmacology, Laboratory of Functional Genomic, CNRS unité propre de Recherche 2580, Montpellier, France
- Cis Bio International, Bagnols-sur-Cèze, France
- Co-last authors
Correspondence to:
Jean-Philippe Pin, UPR-CNRS 9023, Mecanismes Moleculaires des, Communications Cellulaires, CCIPE, Rue de la Cardonille 141, 34094 Montpellier Cedex 5, France. Tel.: +33 467 14 2988; Fax: +33 467 54 2432; E-mail: jppin@ccipe.cnrs.fr
Jaroslav Blahos, Department of Molecular Pharmacology, Institute of Experimental Medicine, Czech Academy of Science, Videnska 1083, 142 20 Prague 4, Czech Republic. Tel.: +420 2 96 44 2725; Fax: +420 2 96 44 2109; E-mail: blahos@seznam.cz
aThese authors contributed equally to this work
Received 10 August 2004; Accepted 23 December 2004
Abstract
G-protein-coupled receptors (GPCRs) have been shown to form dimers, but the relevance of this phenomenon in G-protein activation is not known. Among the large GPCR family, metabotropic glutamate (mGlu) receptors are constitutive dimers. Here we examined whether both heptahelical domains (HDs) are turned on upon full receptor activation. To that aim, we measured G-protein coupling efficacy of dimeric mGlu receptors in which one subunit bears specific mutations. We show that a mutation in the third intracellular loop (i3 loop) known to prevent G-protein activation in a single subunit decreases coupling efficacy. However, when a single HD is blocked in its inactive state using an inverse agonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), no decrease in receptor activity is observed. Interestingly, in a receptor dimer in which the subunit that binds MPEP is mutated in its i3 loop, MPEP enhances agonist-induced activity, reflecting a 'better' activation of the adjacent HD. These data are consistent with a model in which a single HD is turned on upon activation of such homodimeric receptors and raise important issues in deciphering the functional role of GPCR dimer formation for G-protein activation.
Keywords:
- allostery,
- G-protein coupling,
- metabotropic glutamate receptors,
- receptor activation
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