G-protein-independent signaling mediated by metabotropic glutamate receptors

Nat Neurosci. 1999 Dec;2(12):1070-7. doi: 10.1038/15996.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / metabolism
  • Adenosine / pharmacology
  • Amino Acid Sequence
  • Amino Acid Transport System X-AG
  • Animals
  • Cations / metabolism
  • Electric Conductivity
  • Electric Stimulation
  • Enzyme Activation
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • GABA-B Receptor Antagonists
  • Heterotrimeric GTP-Binding Proteins / agonists
  • Heterotrimeric GTP-Binding Proteins / antagonists & inhibitors
  • Heterotrimeric GTP-Binding Proteins / physiology*
  • Mossy Fibers, Hippocampal / drug effects
  • Mossy Fibers, Hippocampal / physiology
  • Organ Culture Techniques
  • Potassium / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • Protein Tyrosine Phosphatases / metabolism
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / physiology*
  • Rats
  • Rats, Wistar
  • Receptors, GABA-B / physiology
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / metabolism*
  • Signal Transduction* / drug effects
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism*

Substances

  • ATP-Binding Cassette Transporters
  • Amino Acid Transport System X-AG
  • Cations
  • Excitatory Amino Acid Antagonists
  • GABA-B Receptor Antagonists
  • Receptors, GABA-B
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • src-Family Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases
  • Heterotrimeric GTP-Binding Proteins
  • Adenosine
  • Potassium