Co-activation of the phosphatidylinositol-3-kinase/Akt signaling pathway by N-methyl-D-aspartate and TrkB receptors in cerebellar granule cell neurons |
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Authors: | Zhu D Lipsky R H Marini A M |
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Institution: | (1) Department of Neurology and Neuroscience, Uniformed Services University of the Health Sciences, Bethesda, Maryland, U.S.A., US;(2) Section on Molecular Genetics, Laboratory of Neurogenetics, NIAAA, National Institutes of Health, Rockville, Maryland, U.S.A., US |
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Abstract: | Summary. 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.
Received June 29, 2001 Accepted August 6, 2001 Published online June 3, 2002 |
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Keywords: | : N-methyl-D-aspartate Brain-derived neurotrophic factor Rat cerebellar granule cells Phosphatidylinositol 3-kinase/Akt TrkB receptor Neuroprotection |
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