Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways
Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways
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DOI：
10.1038/nn835
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发表时间：
2002-05-01
影响因子：
25
通讯作者：
Bading, H
中科院分区：
文献类型：
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作者：
Hardingham, GE;Fukunaga, Y;Bading, H
在这里，我们报告，突触和突触外NMDA（N-甲基-D-天冬氨酸）受体对CREB（cAMP反应元件结合蛋白）功能，基因调控和神经元存活具有相反的作用。通过突触NMDA受体的钙离子进入诱导CREB活性和脑源性神经营养因子（BDNF）基因表达的强烈刺激L型钙通道。相比之下，钙离子通过突触外NMDA受体进入，触发浴谷氨酸暴露或缺氧/缺血条件下，激活了一般和占主导地位的CREB关闭通路，阻断诱导BDNF表达。突触NMDA受体具有抗凋亡活性，而突触外NMDA受体的刺激引起线粒体膜电位（谷氨酸诱导的神经元损伤的早期标志物）的损失和细胞死亡。特异性阻断突触外NMDA受体可有效预防卒中和其他与谷氨酸毒性相关的神经病理学状况后的神经元丢失。
Here we report that synaptic and extrasynaptic NMDA (N-methyl-D-aspartate) receptors have opposite effects on CREB (cAMP response element binding protein) function, gene regulation and neuron survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF) gene expression as strongly as did stimulation of L-type calcium channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activated a general and dominant CREB shut-off pathway that blocked induction of BDNF expression. Synaptic NMDA receptors have anti-apoptotic activity, whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an early marker for glutamate-induced neuronal damage) and cell death. Specific blockade of extrasynaptic NMDA receptors may effectively prevent neuron loss following stroke and other neuropathological conditions associated with glutamate toxicity.