Phosphatidylinositol 3-kinase is a central mediator of NMDA receptor signalling to MAP kinase (Erk1/2), Akt/PKB and CREB in striatal neurones

J Neurochem. 2002 Jan;80(2):239-54. doi: 10.1046/j.0022-3042.2001.00699.x.


Ca2+ influx through NMDA receptors can initiate molecular changes in neurones which may underlie synaptic plasticity, neuronal development, survival and excitotoxicity. Signalling through the MAP kinase (Erk1/2) cascade may be central to these processes. We previously demonstrated that Ca2+-permeable AMPA receptors activate Erkl/2 through a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent mechanism. We now report that NMDA receptor activation of Erk1/2 was also blocked by inhibitors of PI 3-kinase (LY 294002, wortmannin). In addition, pre-treatment of neurones with pertussis toxin inhibited NMDA-induced Erk1/2 activation, indicating a role for heterotrimeric Gi/o proteins. PI 3-kinase directs activation of the serine-threonine kinase Akt (PKB). Treatment of striatal neurones with glutamate induced a rapid Ca2+-dependent and PI 3-kinase-dependent phosphorylation of Akt (Ser473), which was not blocked by the Mek inhibitors PD98059 or U0126. Targets for Erk1/2 and Akt pathways include transcription factors. Glutamate-induced phosphorylation of cAMP response element binding protein (CREB; Ser133) was partially blocked with either PD98059, U0126, LY294002 or wortmannin but was very strongly inhibited on co-application of LY294002 and PD98059. We propose that NMDA receptor stimulation can activate Erk1/2 and Akt signalling pathways in a PI 3-kinase dependent manner which may target CREB in the nucleus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Calmodulin / metabolism
  • Cells, Cultured
  • Corpus Striatum / cytology
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • GTP-Binding Proteins / metabolism
  • Glutamic Acid / pharmacology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Neurons / cytology
  • Neurons / enzymology*
  • Pertussis Toxin
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-raf / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Serine / metabolism
  • Virulence Factors, Bordetella / pharmacology
  • ras Proteins / metabolism


  • Calmodulin
  • Cyclic AMP Response Element-Binding Protein
  • Proto-Oncogene Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Virulence Factors, Bordetella
  • Glutamic Acid
  • Serine
  • Pertussis Toxin
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-raf
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • GTP-Binding Proteins
  • ras Proteins
  • Calcium