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Hydrogen peroxide‐mediated phosphorylation of ERK1/2,
Akt/PKB and JNK in cortical neurones: dependence
on Ca 2+ and PI3‐kinase
Author(s) -
Crossthwaite Andrew J.,
Hasan Sumaera,
Williams Robert J.
Publication year - 2002
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 - 10.1046/j.0022-3042.2001.00637.x
Subject(s) - protein kinase b , phosphorylation , kinase , oxidative stress , extracellular , chemistry , microbiology and biotechnology , neurotoxicity , nmda receptor , creb , biology , biochemistry , receptor , toxicity , gene , transcription factor , organic chemistry
Primary cortical neurones exposed to an oxidative insult in the form of hydrogen peroxide (H 2 O 2 ) for 30 min showed a concentration‐dependent increase in oxidative stress followed by␣a␣delayed NMDA receptor‐dependent cell death measured␣24 h later. Extracellular signal‐regulated protein kinase (ERK1/2), c‐jun N‐terminal kinase (JNK) and the kinase Akt/PKB may regulate neuronal viability in response to oxidative insults. Using phospho‐specific antibodies, a 15‐min stimulation of neurones with H 2 O 2 (100 µ m −1 m m ) produced a concentration‐dependent phosphorylation of ERK1/2 and Akt/PKB that was partly dependent on extracellular Ca 2+ and phosphatidylinositol 3‐kinase (PI3‐K). Higher concentrations of H 2 O 2 (1 m m ) also stimulated a phosphorylation of JNK which was totally dependent on extracellular Ca 2+ but not PI3‐K. H 2 O 2 ‐induced phosphorylation of ERK1/2, Akt/PKB or JNK were unaffected by the NMDA channel blocker MK801. Blocking ERK1/2 activation with the upstream inhibitor U0126 (10 µ m ) enhanced H 2 O 2 ‐induced (100–300 µ m range) neurotoxicity and inhibited H 2 O 2 ‐mediated phosphorylation of the cyclic AMP regulatory binding protein (CREB), suggesting that ERK1/2 signals to survival under these conditions. At higher concentrations (m m ), H 2 O 2 ‐stimulated a phosphorylation of c‐jun. It is likely, therefore, that subjecting neurones to moderate oxidative‐stress recruits pro‐survival signals to CREB but during severe oxidative stress pro‐death signals through JNK and c‐jun are dominant.