Phosphorylation of cAMP response element-binding protein in hippocampal neurons as a protective response after exposure to glutamate in vitro and ischemia in vivo
Phosphorylation of cAMP response element-binding protein in hippocampal neurons as a protective response after exposure to glutamate in vitro and ischemia in vivo
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DOI：
10.1523/jneurosci.21-23-09204.2001
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发表时间：
2001-12-01
影响因子：
5.3
通讯作者：
Matsumoto, M
中科院分区：
文献类型：
--
作者：
Mabuchi, T;Kitagawa, K;Matsumoto, M
虽然越来越多的证据表明cAMP反应元件结合蛋白(cAMP Response Element-Binding Protein，CREB)的磷酸化不仅介导突触的可塑性，而且还参与某些神经元的存活，但代谢损伤后诱导的CREB磷酸化是否导致CRE介导的基因转录以及是否参与细胞存活仍不确定。在本研究中，我们阐明：(1)在沙土鼠全脑缺血模型中，给予MK801可消除预适应缺血后诱导的海马神经元CREB磷酸化和缺血耐受；(2)MK801和钙调素依赖蛋白激酶(CaMK)II和IV的抑制剂可抑制培养神经元在谷氨酸暴露后诱导的CREB磷酸化；(3)CaMK II-IV或CRE诱骗寡核苷酸的抑制剂可抑制bcl2的表达上调，并加速谷氨酸诱导的神经元损伤。(4)在带有Cre-LacZ报告基因的转基因小鼠中，缺血后海马神经元和谷氨酸暴露后培养的神经元中CREB被诱导磷酸化，随后Cre介导的基因转录。我们的结果表明，缺血和谷氨酸暴露后神经元CREB的磷酸化是由NMDA受体门控的钙内流和随后激活的CaMK II-IV诱导的，代谢应激后的CREB磷酸化可能通过Cre介导的基因诱导而显示出神经保护作用。
Although accumulating evidence indicates that cAMP response element-binding protein (CREB) phosphorylation mediates not only synaptic plasticity but also survival of certain neurons, it remains uncertain whether CREB phosphorylation induced after metabolic insult leads to CRE-mediated gene transcription and is involved in cell survival or not. In the present study, we clarified that (1) CREB phosphorylation and ischemic tolerance induced after preconditioning ischemia in the hippocampal neurons was abolished by MK801 administration in gerbil global ischemia model, (2) CREB phosphorylation induced after exposure to glutamate in cultured neurons was inhibited by removal of extracellular calcium, by MK801 and by an inhibitor of calcium-calmodulin-dependent protein kinase (CaMK) II and IV, (3) inhibitor of CaMK II-IV or CRE-decoy oligonucleotide suppressed upregulation of BCL-2 expression and accelerated neuronal damage after exposure to glutamate, and (4) CREB phosphorylation induced in the hippocampal neurons after ischemia and in cultured neurons after exposure to glutamate was followed by CRE-mediated gene transcription in transgenic mice with a CRE-LacZ reporter. Our results suggest that CREB phosphorylation in neurons after ischemia and exposure to glutamate is induced by NMDA receptor-gated calcium influx and subsequent activation of CaMK II-IV and that CREB phosphorylation after metabolic stress might show a neuroprotective response through CRE-mediated gene induction.