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Phosphatidylinositol 3‐kinase is a central mediator of NMDA receptor signalling to MAP kinase (Erk1/2), Akt/PKB and CREB in striatal neurones
Author(s) -
Perkinton Michael S.,
Ip James,
Wood Gemma L.,
Crossthwaite Andrew J.,
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.0022-3042.2001.00699.x
Subject(s) - wortmannin , protein kinase b , microbiology and biotechnology , ampa receptor , creb , biology , ly294002 , kinase , chemistry , signal transduction , nmda receptor , biochemistry , receptor , transcription factor , gene
Ca 2+ influx through NMDA receptors can initiate molecular changes in neurones which may underlie synaptic plasticity, neuronal development, survival and excitotoxicity. Signalling through the MAP kinase (Erk1/2) cascade may be central to␣these processes. We previously demonstrated that Ca 2+ ‐permeable AMPA receptors activate Erk1/2 through a phosphatidylinositol 3‐kinase (PI 3‐kinase)‐dependent mechanism. We now report that NMDA receptor activation of Erk1/2 was also blocked by inhibitors of PI 3‐kinase (LY 294002, wortmannin). In addition, pre‐treatment of neurones with pertussis toxin inhibited NMDA‐induced Erk1/2 activation, indicating a role for heterotrimeric G i/o proteins. PI 3‐kinase directs activation of the serine‐threonine kinase Akt (PKB). Treatment of striatal neurones with glutamate induced a rapid Ca 2+ ‐dependent and PI 3‐kinase‐dependent phosphorylation of Akt (Ser473), which was not blocked by the Mek inhibitors PD98059 or U0126. Targets for Erk1/2 and Akt pathways include transcription factors. Glutamate‐induced phosphorylation of cAMP response element binding protein (CREB; Ser133) was partially blocked with either PD98059, U0126, LY294002 or wortmannin but was very strongly inhibited on co‐application of LY294002 and PD98059. We propose that NMDA receptor stimulation can activate Erk1/2 and Akt signalling pathways in a PI 3‐kinase dependent manner which may target CREB in the nucleus.