Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium / metabolism
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Calmodulin / metabolism
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Cells, Cultured
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Corpus Striatum / cytology
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Cyclic AMP Response Element-Binding Protein / metabolism*
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GTP-Binding Proteins / metabolism
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Glutamic Acid / pharmacology
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology*
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Mice
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / metabolism
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Neurons / cytology
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Neurons / enzymology*
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Pertussis Toxin
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-raf / metabolism
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Serine / metabolism
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Virulence Factors, Bordetella / pharmacology
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ras Proteins / metabolism
Substances
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Calmodulin
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Cyclic AMP Response Element-Binding Protein
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Proto-Oncogene Proteins
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Receptors, N-Methyl-D-Aspartate
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Virulence Factors, Bordetella
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Glutamic Acid
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Serine
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Pertussis Toxin
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-raf
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase Kinases
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GTP-Binding Proteins
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ras Proteins
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Calcium