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NMDA neuroprotection against a phosphatidylinositol‐3 kinase inhibitor, LY294002 by NR2B‐mediated suppression of glycogen synthase kinase‐3β‐induced apoptosis
Author(s) -
Habas Agata,
Kharebava Giorgi,
Szatmari Erzsebet,
Hetman Michal
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03543.x
Subject(s) - gsk 3 , neuroprotection , nmda receptor , ly294002 , excitotoxicity , gsk3b , chemistry , kinase , microbiology and biotechnology , biology , pharmacology , glycogen synthase , phosphatidylinositol , phosphorylation , biochemistry , receptor
To identify the intracellular signaling pathways that mediate the pro‐survival activity of NMDA receptors (NMDARs), we studied effects of exogenous NMDA on cultured rat cortical and hippocampal neurons that were treated with a phosphatidylinositol‐3‐kinase (PI3K) inhibitor, LY294002. NMDA at 5 or 10 µ m protected against LY294002‐induced apoptosis, suggesting NMDAR‐mediated activation of a survival signaling pathway that is PI3K‐independent. NR2B‐specific NMDAR blockers antagonized anti‐apoptotic effects of NMDA, indicating a critical role of NR2B NMDARs in the neuroprotection. NMDA at 10 µ m suppressed LY294002‐induced activation of a pro‐apoptotic kinase, glycogen synthase kinase 3β (GSK3β). GSK3β activation by LY294002 was associated with decreased levels of inhibitory GSK3β phosphorylation at the Ser9 residue. However, NMDA did not prevent the LY294002‐mediated decline of phospho‐Ser9 levels. In addition, NMDA inhibited cortical neuron apoptosis induced by the overexpression of either wild type (wt) or Ser9Ala mutant form of GSK3β, suggesting that NMDA suppressed GSK3β in a Ser9‐independent manner. Finally, inhibition of NR2B NMDARs reduced the NMDA protection against overexpression of GSK3βwt. These data indicate that moderate stimulation of NR2B NMDAR protects against inhibition of PI3K by a Ser9‐independent inhibition of the pro‐apoptotic activity of GSK3β. Hence, the activation of NR2B and the Ser9‐independent inhibition of GSK3β are two newly identified elements of the signaling network that mediates the pro‐survival effects of NMDA.