Pláteník J, Kuramoto N, Yoneda Y
Department of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa, Japan.
Life Sci. 2000 Jun 16;67(4):335-64. doi: 10.1016/s0024-3205(00)00632-9.
The N-methyl-D-aspartate (NMDA) subtype of glutamate receptors in the mammalian brain plays a central role in synaptic plasticity underlying refinement of neuronal connections during development, or processes like long-term potentiation (LTP), learning and memory. On the other hand, over-activation of glutamate receptors leading to neurodegeneration has been implicated in major areas of brain pathology. Any sustained effect of a transient NMDA receptor activation is likely to involve signaling to the nucleus and coordinated changes in gene expression. Classically, a set of immediate-early genes is induced first; some of them are themselves transcription factors that control expression of other target genes. This review deals with the induction of Fos, Jun and Egr (Krox) transcription factors in response to NMDA or non-NMDA (AMPA/kainate) ionotropic receptor agonists in vivo or in neuronal cultures in vitro. In addition, the mechanism of induction of a model immediate-early gene c-fos in response to Ca2+ influx through activated NMDA receptors or voltage-sensitive calcium channels is discussed. Both modes of calcium entry induce c-fos via activation of multiple signaling pathways that converge on constitutive transcription factors cAMP-response element-binding protein (CREB), serum response factor (SRF) and a ternary complex factor (TCF), such as Elk-1. In contrast to the traditional view of the NMDA receptor as a ligand-gated calcium channel, whose activation leads to calcium influx and activation of Ca2+/calmodulin-dependent kinases, recent evidence highlights involvement of the Ras/ mitogen-activated protein kinase (MAPK) pathway in the NMDA signaling to the nucleus.
哺乳动物大脑中谷氨酸受体的N-甲基-D-天冬氨酸（NMDA）亚型在发育过程中神经元连接精细化、长期增强（LTP）、学习和记忆等过程所涉及的突触可塑性方面发挥着核心作用。另一方面，谷氨酸受体过度激活导致神经退行性变与大脑病理学的主要领域有关。短暂的NMDA受体激活的任何持续效应可能都涉及向细胞核发出信号以及基因表达的协调变化。传统上，首先诱导一组即早基因；其中一些本身就是控制其他靶基因表达的转录因子。本综述探讨了在体内或体外神经元培养中，Fos、Jun和Egr（Krox）转录因子对NMDA或非NMDA（AMPA/海人藻酸）离子型受体激动剂的应答诱导情况。此外，还讨论了通过激活的NMDA受体或电压敏感性钙通道内流的Ca2+诱导模型即早基因c-fos的机制。两种钙内流模式均通过激活多条信号通路诱导c-fos，这些信号通路汇聚于组成型转录因子环磷酸腺苷反应元件结合蛋白（CREB）、血清反应因子（SRF）和三元复合因子（TCF），如Elk-1。与传统观点认为NMDA受体是配体门控钙通道，其激活导致钙内流和Ca2+/钙调蛋白依赖性激酶激活不同，最近的证据突出了Ras/丝裂原活化蛋白激酶（MAPK）通路在NMDA向细胞核信号传导中的作用。
