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Sci. Signal., 14 August 2012
Vol. 5, Issue 237, p. ra59
[DOI: 10.1126/scisignal.2002720]


Sequential Inter- and Intrasubunit Rearrangements During Activation of Dimeric Metabotropic Glutamate Receptor 1

Veronika Hlavackova1,2,3,4,5, Ulrike Zabel1,2, Daniela Frankova3, Julia Bätz1, Carsten Hoffmann1, Laurent Prezeau4,5, Jean-Philippe Pin4,5*{dagger}, Jaroslav Blahos3*{dagger}, and Martin J. Lohse1,2*{dagger}

1 Institute of Pharmacology and Toxicology, University of Würzburg, 97078 Würzburg, Germany.
2 Rudolf Virchow Center, University of Würzburg, 97078 Würzburg, Germany.
3 Department of Pharmacology, Institute of Molecular Genetics, Czech Academy of Science, 142 20 Prague 4, Czech Republic.
4 University of Montpellier 1 & 2, CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier F-34094, France.
5 INSERM U661, Montpellier F-34094, France.

* These authors contributed equally to this work.

Abstract: The metabotropic glutamate receptor 1 (mGluR1), a class C member of the heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor family, is a constitutive dimer that regulates excitatory neurotransmission. We investigated the role of homodimer formation in mGluR1 activation by examining activation-dependent inter- and intrasubunit conformational changes by fluorescence resonance energy transfer (FRET). We inserted yellow and cyan fluorescent proteins in the second intracellular loop and at the carboxyl terminus of mGluR1 to act as FRET sensors and expressed these proteins in human embryonic kidney 293 cells. Agonist-dependent activation of these mGluR1 chimeras rapidly increased the intersubunit FRET, suggesting rapid movement of the subunits relative to each other. After intersubunit movement, the intrasubunit FRET decreased, reflecting conformational changes within a subunit. Cotransfection of chimeric receptor subunits that were capable or incapable of G protein coupling revealed that only a single subunit assumes an active state in an mGluR1 receptor dimer.

{dagger} To whom correspondence should be addressed. E-mail: lohse{at} (M.J.L.); blahos{at} (J.B.); Jean-Philippe.Pin{at} (J.-P.P.)

Citation: V. Hlavackova, U. Zabel, D. Frankova, J. Bätz, C. Hoffmann, L. Prezeau, J.-P. Pin, J. Blahos, M. J. Lohse, Sequential Inter- and Intrasubunit Rearrangements During Activation of Dimeric Metabotropic Glutamate Receptor 1. Sci. Signal. 5, ra59 (2012).

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