Phosphatidylinositol 3-kinase is a central mediator of NMDA receptor signalling to MAP kinase (Erk1/2), Akt/PKB and CREB in striatal neurones
Article first published online: 27 FEB 2002
Journal of Neurochemistry
Volume 80, Issue 2, pages 239–254, January 2002
How to Cite
Perkinton, M. S., Ip, J., Wood, G. L., Crossthwaite, A. J. and Williams, R. J. (2002), Phosphatidylinositol 3-kinase is a central mediator of NMDA receptor signalling to MAP kinase (Erk1/2), Akt/PKB and CREB in striatal neurones. Journal of Neurochemistry, 80: 239–254. doi: 10.1046/j.0022-3042.2001.00699.x
- Issue published online: 27 FEB 2002
- Article first published online: 27 FEB 2002
- Received June 1, 2001; revised manuscript received September 12, 2001; accepted October 9, 2001.
- G protein;
- MAP kinase;
- PI 3-kinase
Ca2+ 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 Ca2+-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 Gi/o proteins. PI 3-kinase directs activation of the serine-threonine kinase Akt (PKB). Treatment of striatal neurones with glutamate induced a rapid Ca2+-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.