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G-protein-independent signaling mediated by metabotropic glutamate receptors

Nature Neuroscience volume 2, pages 1070–1077 (1999)Cite this article

Abstract

Synaptically released glutamate activates ionotropic and metabotropic receptors at central synapses. Metabotropic glutamate receptors (mGluRs) are thought to modulate membrane conductances through transduction cascades involving G proteins. Here we show, in CA3 pyramidal cells from rat hippocampus, that synaptic activation of type 1 mGluRs by mossy fiber stimulation evokes an excitatory postsynaptic response independent of G-protein function, while inhibiting an afterhyperpolarization current through a G-protein-coupled mechanism. Experiments using peptide activators and specific inhibitors identified a Src-family protein tyrosine kinase as a component of the G-protein-independent transduction pathway. These results represent the first functional evidence for a dual signaling mechanism associated with a heptahelical receptor such as mGluR1, in which intracellular transduction involves activation of either G proteins or tyrosine kinases.

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Figure 1: Mossy-fiber-specific activation of a slow EPSC.
Figure 2: The slow EPSC is mediated by mGluR1.
Figure 3: The G-protein inhibitors NEM and GDPβS block adenosine responses, but not the mGluR EPSC.
Figure 4: Uncaging of GTPγS inhibits GABAB receptor IPSCs without affecting mGluR EPSCs.
Figure 5: Tyrosine kinase inhibitors suppress the mGluR EPSC.
Figure 6: Tyrosine phosphatase inhibition prolongs decay of the mGluR-mediated response.
Figure 7: Direct stimulation of Src kinase occludes mGluR1 activation.
Figure 8: Divergent signaling by mGluR1.

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Acknowledgements

We thank L. Heeb, L. Rietschin and R. Schöb for technical assistance, F. Pouille for the help with acute slices and D. Jabaudon, A. Lüthi, F. Loup, O. Raineteau and N. Arnth-Jensen for discussions and for reading the manuscript. We also thank N. Guérineau for initial experiments with tyrosine kinase inhibitors. Supported by Novartis (C.H.), the Prof. Dr. Max Cloëtta Foundation (U.G.) and a Swiss National Science Foundation grant 31-45547.95 (U.G.).

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  1. Brain Research Institute, University of Zurich, Winterthurerstrasse 190, Zurich, CH-8057, Switzerland

    Christian Heuss, Massimo Scanziani, Beat H. Gähwiler & Urs Gerber

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Correspondence to Christian Heuss.

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Heuss, C., Scanziani, M., Gähwiler, B. et al. G-protein-independent signaling mediated by metabotropic glutamate receptors . Nat Neurosci 2, 1070–1077 (1999). https://doi.org/10.1038/15996

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