Phosphatidylinositol 3-kinase is a central mediator of NMDA receptor signalling to MAP kinase (Erk1/2), Akt/PKB and CREB in striatal neurones.
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.
Perkinton
Michael S
MS
Centre for Neuroscience Research, Guy's, King's and St Thomas' School of Biomedical Sciences, London, UK.
Ip
James K
JK
Wood
Gemma L
GL
Crossthwaite
Andrew J
AJ
Williams
Robert J
RJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism
D002118:Calcium; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002147:Calmodulin; D017362:Cyclic AMP Response Element-Binding Protein; D019204:GTP-Binding Proteins; D018698:Glutamic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D010566:Virulence Factors, Bordetella; D018631:ras Proteins