Co-activation of the phosphatidylinositol-3-kinase/Akt signaling pathway by N-methyl-D-aspartate and TrkB receptors in cerebellar granule cell neurons.
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.
Zhu
D
D
Department of Neurology and Neuroscience, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
Lipsky
R H
RH
Marini
A M
AM
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002227:Carbazoles / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000378:metabolism; D002867:Chromones / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D026121:Indole Alkaloids; D009025:Morpholines / Q000378:metabolism; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D002867:Chromones; D016291:Dizocilpine Maleate; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D026121:Indole Alkaloids; D009025:Morpholines; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020813:Receptor, trkB; D016194:Receptors, N-Methyl-D-Aspartate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C049985:staurosporine aglycone; C494920:Akt1 protein, rat