Native group-III metabotropic glutamate receptors are coupled to the mitogen-activated protein kinase/phosphatidylinositol-3-kinase pathways

J Neurochem. 2002 Jul;82(2):216-23. doi: 10.1046/j.1471-4159.2002.00929.x.

Abstract

We used cultured cerebellar granule cells to examine whether native group-III metabotropic glutamate (mGlu) receptors are coupled to the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI-3-K) pathways. Cultured granule cells responded to the group-III mGlu receptor agonist, L-2-amino-4-phosphonobutanoate (l-AP4), with an increased phosphorylation and activity of MAPKs (ERK-1 and -2) and an increased phosphorylation of the PI-3-K target, protein kinase B (PKB/AKT). These effects were attenuated by the group-III antagonists, alpha-methyl-serine-O -phosphate (MSOP) and (R,S )-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG), or by pretreatment of the cultures with pertussis toxin. l-AP4 also induced the nuclear translocation of beta-catenin, a downstream effector of the PI-3-K pathway. To assess the functional relevance of these mechanisms we examined the ability of l-AP4 to protect granule cells against apoptosis by trophic deprivation, induced by lowering extracellular K(+) from 25 to 10 mm. Neuroprotection by l-AP4 was attenuated by MSOP and abrogated by the compounds PD98059 and UO126, which inhibit the MAPK pathway, or by the compound LY294002, which inhibits the PI-3-K pathway. Taken together, these results show for the first time that native group-III mGlu receptors are coupled to MAPK and PI-3-K, and that activation of both pathways is necessary for neuroprotection mediated by this particular class of receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Aminobutyrates / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cells, Cultured
  • Cytoskeletal Proteins / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • MAP Kinase Signaling System / physiology
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neurons / drug effects
  • Neurons / enzymology
  • Neuroprotective Agents / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Potassium / metabolism
  • Potassium / pharmacology
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / metabolism*
  • Signal Transduction / physiology*
  • Trans-Activators*
  • beta Catenin

Substances

  • Aminobutyrates
  • Ctnnb1 protein, rat
  • Cytoskeletal Proteins
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Neuroprotective Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Receptors, Metabotropic Glutamate
  • Trans-Activators
  • beta Catenin
  • Akt1 protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • 2-amino-4-phosphonobutyric acid
  • Potassium

Grants and funding