Abstract
Neuroprotective concentrations of N-methyl-D-aspartate (NMDA) promote survival of cerebellar granule cell neurons against glutamate excitotoxicity through a TrkB receptor-mediated brain-derived neurotrophic factor (BDNF) autocrine loop. However, the intracellular signaling pathway(s) are not clear. Our results show that PI-3 kinase/Akt is activated by either NMDA or BDNF displaying differential kinetics. BDNF and NMDA increased Akt phosphorylation within 5 minutes but maximal activation by NMDA was observed at 3 hours. Akt phosphorylation was completely blocked by the PI-3 kinase inhibitor LY294002. NMDA-mediated activation of Akt was completely blocked by MK-801 and partially blocked by the TrkB receptor inhibitor, K252a, indicating the requirement of TrkB receptors for maximal activation by NMDA. In contrast, BDNF-induced Akt phosphorylation was abolished by K252a, but not by the addition of MK-801. Therefore, the PI-3 kinase/Akt pathway is co-activated by NMDA and TrkB receptors. The kinetics of BDNF and NMDA-mediated activation of PI-3 kinase/Akt suggests that they have different roles in intraneuronal time-related events.
MeSH terms
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Animals
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Brain-Derived Neurotrophic Factor / metabolism
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Carbazoles / metabolism
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Cells, Cultured
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Cerebellum / cytology*
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Cerebellum / metabolism
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Chromones / metabolism
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Dizocilpine Maleate / metabolism
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Enzyme Activation
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Enzyme Inhibitors / metabolism
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Excitatory Amino Acid Agonists / metabolism
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Excitatory Amino Acid Antagonists / metabolism
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Indole Alkaloids
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Morpholines / metabolism
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N-Methylaspartate / metabolism
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Neurons / cytology
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Neurons / metabolism*
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Neuroprotective Agents / metabolism
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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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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Rats
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Rats, Sprague-Dawley
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Receptor, trkB / metabolism*
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Signal Transduction / physiology*
Substances
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Brain-Derived Neurotrophic Factor
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Carbazoles
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Chromones
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Enzyme Inhibitors
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Excitatory Amino Acid Agonists
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Excitatory Amino Acid Antagonists
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Indole Alkaloids
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Morpholines
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Neuroprotective Agents
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Receptors, N-Methyl-D-Aspartate
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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N-Methylaspartate
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Dizocilpine Maleate
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staurosporine aglycone
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Receptor, trkB
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt