Activation of the extracellular signal-regulated kinase 2 by metabotropic glutamate receptors

Eur J Neurosci. 1999 Jun;11(6):2073-2082. doi: 10.1046/j.1460-9568.1999.00626.x.


Activation of metabotropic glutamate receptors (mGluRs) leads to modulation of a variety of second messenger pathways probably including the mitogen-activated protein kinase (MAPK) extracellular signal-regulated protein kinases (ERK). MAPK play a key role in the control of cellular responses to changes in the external environment by regulating transcriptional activity and the phosphorylation state of several cytoplasmic targets. In this study, Chinese hamster ovary (CHO) cells permanently transfected with rat mGluR1a, mGluR2 and mGluR4 were employed as a model to examine the activation of MAPK by glutamate through mGluRs. All three mGluR subtypes rapidly stimulated ERK activation. In particular, mGluR1a and mGluR2 preferentially mediated phosphorylation and activation of ERK2 in a pertussis toxin (PTX)-sensitive and concentration-dependent manner. The activation was blocked completely by pretreatment with the antagonist (rs)-alpha-methyl-4-carboxyphenylglycine (MCPG) or with the MEK inhibitor PD098059. Furthermore, mGluR1a-mediated ERK activation was suppressed by the depletion of endogenous protein kinase C (PKC) activity and by the PKC inhibitors staurosporine and calphostin C, but not chelerythrine. When cAMP was elevated in mGluR2-expressing cells, by forskolin or dibutyryl-cAMP, slight elevation of ERK activity was observed. However, glutamate-stimulated ERK activation remained unaffected. In these cells, the phosphatidylinositol 3 kinase (PI3K) inhibitor wortmannin produced a significant, albeit only partial, inhibition of mGluR2-mediated ERK activation. These findings raise the possibility of a MAPK cascade involvement in glutamate-dependent neuronal plasticity mediated through stimulation of mGluRs.

MeSH terms

  • Animals
  • Benzoates / pharmacology
  • CHO Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cricetinae
  • Cyclic AMP / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Extracellular Space / enzymology*
  • GTP-Binding Proteins / drug effects
  • GTP-Binding Proteins / physiology
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Intracellular Membranes / metabolism
  • MAP Kinase Kinase 1
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases*
  • Mitogen-Activated Protein Kinases*
  • Pertussis Toxin
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase C / physiology
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Rats
  • Receptors, Metabotropic Glutamate / physiology*
  • Signal Transduction / physiology*
  • Virulence Factors, Bordetella / pharmacology


  • Benzoates
  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Metabotropic Glutamate
  • Virulence Factors, Bordetella
  • alpha-methyl-4-carboxyphenylglycine
  • Cyclic AMP
  • Pertussis Toxin
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • Mitogen-Activated Protein Kinase Kinases
  • GTP-Binding Proteins
  • Glycine