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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

2002; Wiley; Volume: 80; Issue: 2 Linguagem: Inglês

10.1046/j.0022-3042.2001.00699.x

1471-4159

Michael S. Perkinton, James E. Ip, Gemma L. Wood, Andrew J. Crossthwaite, Robert J. Williams,

Cell death mechanisms and regulation

Abstract 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.