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Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer

Nature volume 411, pages 962–965 (2001)Cite this article

Abstract

G-protein-coupled receptors (GPCRs) transduce signals from extracellular transmitters to the inside of the cell by activating G proteins. Mutation and overexpression of these receptors have revealed that they can reach their active state even in the absence of agonist, as a result of a natural shift in the equilibrium between their inactive and active conformations1. Such agonist-independent (constitutive) activity has been observed for the glutamate GPCRs (the metabotropic glutamate receptors mGluR1a and mGluR5) when they are overexpressed in heterologous cells2. Here we show that in neurons, the constitutive activity of these receptors is controlled by Homer proteins, which bind directly to the receptors' carboxy-terminal intracellular domains3,4. Disruption of this interaction by mutagenesis or antisense strategies, or expression of endogenous Homer1a (H1a), induces constitutive activity in mGluR1a or mGluR5. Our results show that these glutamate GPCRs can be directly activated by intracellular proteins as well as by agonists.

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Figure 1: Knock-down of H3 results in constitutive mGluR1a activity.
Figure 2: Interaction between mGluR5a and H3 prevents constitutive receptor activity.
Figure 3: Knock-down of H3.
Figure 4: Endogenous or recombinant H1a induces constitutive mGluR1a activity.

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Acknowledgements

We thank F. Gasparini and R. Kuhn (Novartis Parma) for providing MPEP; D. Robbe for preliminary experiments on mGluR5 mutants; and J. Perroy, C. de Cole and C. Becamel for help in improving our transfection method and experiments with HEK-293 cells and western blots. This work was supported by grants from CNRS, Bayer (France) and FRM. L.F. was also supported by AFM, J.B. by GIP-HMR, and J.P.P. by Retina France and the French Ministry. F.A. holds a grant from Sanofi-Synthelabo (France).

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Authors and Affiliations

  1. CNRS-UPR 9023, CCIPE, 141 Rue de la Cardonille, Montpellier, 34000, France

    F. Ango, L. Prézeau, J. P. Pin, J. Bockaert & L. Fagni

  2. BAYER AG, Pharma Research, Wuppertal, 42096, Germany

    T. Muller

  3. Department of Neurosciences, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    J. C. Tu, B. Xiao & P. F. Worley

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  1. F. Ango
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Correspondence to L. Fagni.

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Ango, F., Prézeau, L., Muller, T. et al. Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer. Nature 411, 962–965 (2001). https://doi.org/10.1038/35082096

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