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Heptahelical domain of metabotropic glutamate receptor 5 behaves like rhodopsin-like receptors.

Abstract : 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 (mGlu(5)) displays the same agonist-independent constitutive activity as the wild-type receptor. Moreover, we show that the noncompetitive 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 mGlu(5) HD 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.
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Contributor : Cyril Goudet <>
Submitted on : Friday, September 5, 2008 - 4:16:01 PM
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Cyril Goudet, Florence Gaven, Julie Kniazeff, Claire Vol, Jianfeng Liu, et al.. Heptahelical domain of metabotropic glutamate receptor 5 behaves like rhodopsin-like receptors.. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2004, 101 (1), pp.378-83. ⟨10.1073/pnas.0304699101⟩. ⟨inserm-00319003⟩

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