Phosphorylation of cAMP response element-binding protein in hippocampal neurons as a protective response after exposure to glutamate in vitro and ischemia in vivo

Although accumulating evidence indicates that cAMP response element-binding protein (CREB) phosphorylation mediates not only synaptic plasticity but a lso survival of certain neurons, it remains uncertain whether CREB phosphor ylation induced after metabolic insult leads to CRE-mediated gene transcrip tion and is involved in cell survival or not. In the present study, we clar ified that (1) CREB phosphorylation and ischemic tolerance induced after pr econditioning ischemia in the hippocampal neurons was abolished by MK801 ad ministration in gerbil global ischemia model, (2) CREB phosphorylation indu ced after exposure to glutamate in cultured neurons was inhibited by remova l of extracellular calcium, by MK801 and by an inhibitor of calcium-calmodu lin-dependent protein kinase (CaMK) II and IV, (3) inhibitor of CaMK II-IV or CRE-decoy oligonucleotide suppressed upregulation of BCL-2 expression an d accelerated neuronal damage after exposure to glutamate, and (4) CREB pho sphorylation induced in the hippocampal neurons after ischemia and in cultu red neurons after exposure to glutamate was followed by CRE-mediated gene t ranscription in transgenic mice with a CRE-LacZ reporter. Our results sugge st that CREB phosphorylation in neurons after ischemia and exposure to glut amate is induced by NMDA receptor-gated calcium influx and subsequent activ ation of CaMK II-IV and that CREB phosphorylation after metabolic stress mi ght show a neuroprotective response through CRE-mediated gene induction.