Heptahelical Domain of Metabotropic Glutamate Receptor 5 Behaves Like Rhodopsin-like Receptors

Although agonists bind directly in the heptahelical domain (HD) of most class-I rhodopsin-like G protein coupled receptors (GPCRs), class-III agonists bind in the extracellular domain of their receptors. Indeed, the latter possess a large extracellular domain composed of a cysteine-rich domain and a...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2004-01, Vol.101 (1), p.378-383
Hauptverfasser: Goudet, Cyril, Gaven, Florence, Kniazeff, Julie, Vol, Claire, Liu, Jiangfeng, Cohen-Gonsaud, Martin, Acher, Francine, Prézeau, Laurent, Pin, Jean Philippe
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Sprache:eng
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Zusammenfassung:Although agonists bind directly in the heptahelical domain (HD) of most class-I rhodopsin-like G protein coupled receptors (GPCRs), class-III agonists bind in the extracellular domain of their receptors. Indeed, the latter possess a large extracellular domain composed of a cysteine-rich domain and a Venus flytrap module. Both the low sequence homology and the structural organization of class-III GPCRs raised the question of whether or not the HD of these receptors functions the same way as rhodopsin-like GPCRs. Here, we show that the HD of metabotropic glutamate receptor 5 (mGlu5) displays the same agonist-independent constitutive activity as the wild-type receptor. Moreover, we show that the non-competitive antagonist MPEP [2-methyl-6-(phenylethynyl)-pyridine hydrochloride] and the positive allosteric modulator DFB (3,3′-difluorobenzaldazine) act as inverse agonist and full agonist, respectively, on the mGlu5HD in the absence of the extracellular domain. This finding illustrates that, like rhodopsin-like receptors, the HD of mGluRs can constitutively couple to G proteins and be negatively and positively regulated by ligands. These data show that the HD of mGluRs behave like any other class-I GPCRs in terms of G protein coupling and regulation by various types of ligands.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0304699101