Akt mediates the anti-apoptotic effect of NMDA but not that induced by potassium depolarization in cultured cerebellar granule cells.
Apoptosis of cultured cerebellar granule neurons (CGNs) deprived of serum is prevented by K+ depolarization or moderate concentrations of N-methyl-d-aspartate (NMDA). Here, we have examined the role of the serine/threonine kinase Akt in these protective effects. The exposure of mouse CGNs to NMDA or K+ depolarization increased the phosphorylation of Akt, compared with that measured in cells incubated in a physiological K+ concentration. Only the NMDA-evoked response was reduced by inhibitors of phosphatidylinositol 3-kinase (wortmannin and LY294002) and mitogen-activated protein kinase (PD98059 and U0126). Similarly, the capacity of NMDA to inhibit apoptosis of CGNs deprived of serum was greatly reduced by these inhibitors as well as by the transfection of neurons with a catalytically inactive mutant of Akt, whereas the protective effect of K+ depolarization remained unaffected. These findings indicate that K+ depolarization and NMDA activate Akt through different signalling pathways in CGNs. Moreover, Akt mediates the anti-apoptotic effect of NMDA, but not that evoked by K+ depolarization.
Lafon-Cazal
Mireille
M
UPR CNRS 9023, CCIPE, 141, rue de la Cardonille, 34094 Montpellier Cedex 5, France. lafon@montp.inserm.fr
Perez
Virgili
V
Bockaert
Joël
J
Marin
Philippe
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D011518:Proto-Oncogene Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011188:Potassium