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Organization and functions of mGlu and GABAB receptor complexes

Abstract

The neurotransmitters glutamate and γ-aminobutyric acid (GABA) transmit synaptic signals by activating fast-acting ligand-gated ion channels and more slowly acting G-protein-coupled receptors (GPCRs). The GPCRs for these neurotransmitters, metabotropic glutamate (mGlu) and GABAB receptors, are atypical GPCRs with a large extracellular domain and a mandatory dimeric structure. Recent studies have revealed how these receptors are activated through multiple allosteric interactions between subunit domains. It emerges that the molecular complexity of these receptors is further increased through association with trafficking, effector and regulatory proteins. The structure and composition of these receptors present opportunities for therapeutic intervention in mental health and neurological disorders.

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Figure 1: Oligomerization of GABABRs and mGluRs.
Figure 2: Structural models of dimeric mGluRs and GABABRs in the inactive and active states.
Figure 3: Ribbon views of the 7TMDs of mGlu1, mGlu5 and the β2-adrenergic receptor (β2-AR), with bound FITM, mavoglurant and (S)-carazolol.
Figure 4: Opportunities for influencing mGluR and GABABR activity through orthosteric and allosteric binding sites or through interference with protein–protein interactions of receptor components.

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Acknowledgements

We thank M. Gassmann, J. Kniazeff and X. Rovira for discussions and help with the figures. This work was supported by grants of the Swiss Science Foundation (3100A0-117816) the National Center for Competences in Research (NCCR) ‘Synapsy, Synaptic Basis of Mental Health Disease’ to B.B., and by grants from the Agence National de la Recherche (ANR-12-BSV2-0015; ANR-13-RPIB-0009), the Fondation Recherche Médicale (FRM DEQ20130326522), the Fondation Bettencourt Schueller, and the Fond Unique Interministériel of the French government (FUI, Cell2Lead project) to J.-P.P.

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Correspondence to Jean-Philippe Pin or Bernhard Bettler.

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Reviewer Information Nature thanks K. Gregory, F. Marshall and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Pin, JP., Bettler, B. Organization and functions of mGlu and GABAB receptor complexes. Nature 540, 60–68 (2016). https://doi.org/10.1038/nature20566

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