N-甲基-D-天冬氨酸（NMDA）受体偏好的细胞内信号通路从 ERK1/2 蛋白向 p38 丝裂原活化蛋白激酶的转换导致 NMDA 神经毒性的发育变化。
Switching of N-methyl-D-aspartate (NMDA) receptor-favorite intracellular signal pathways from ERK1/2 protein to p38 mitogen-activated protein kinase leads to developmental changes in NMDA neurotoxicity.
机构信息
Key Laboratory of Molecular Neurobiology, Ministry of Education, Institute of Neuroscience, Neuroscience Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
出版信息
J Biol Chem. 2011 Jun 10;286(23):20175-93. doi: 10.1074/jbc.M110.188854. Epub 2011 Apr 7.
Excitotoxicity mediated by overactivation of N-methyl-D-aspartate receptors (NMDARs) has been implicated in a variety of neuropathological conditions in the central nervous system (CNS). It has been suggested that N-methyl-D-aspartate (NMDA) neurotoxicity is developmentally regulated, but the definite pattern of the regulation has been controversial, and the underlying mechanism remains largely unknown. Here, we show that NMDA treatment leads to significant cell death in mature (9 and 12 days in vitro) hippocampal neurons or hippocampi of young postnatal day 12 and adult rats but not in immature (3 and 6 days in vitro) neurons or embryonic day 18 and neonatal rat hippocampi. In contrast, NMDA promotes survival of immature neurons against tropic deprivation. Interestingly, it is found that NMDA preferentially activates p38 MAPK in mature neuron and adult rat hippocampus, but it favors ERK1/2 activation in immature neuron and postnatal day 0 rat hippocampus. Moreover, it is shown that NMDA neurotoxicity in mature neuron is mediated via p38 MAPK activation, and neuroprotection in immature neuron is mediated via ERK1/2 activation, whereas all these effects are NR2B-containing NMDAR-dependent, as well as Ca(2+)-dependent. We also revealed that mature and immature neurons showed no difference in the amplitude of NMDA-induced intracellular calcium (Ca(2+)) increase. However, the basal level of Ca(2+) is shown to elevate with the maturation of neuron, and this elevation is attributable to the changes in NMDA neurotoxicity but not to the switch of the NMDAR signaling pathway. Taken together, our results suggest that a switch of NMDA receptor-favorite intracellular signal pathways from ERK1/2 to p38 MAPK and the elevated basal level of Ca(2+) with age might be critical for the developmental changes in NMDA neurotoxicity in the hippocampal neuron.
谷氨酸能毒性介导的 NMDA 受体（NMDAR）过度激活与中枢神经系统（CNS）中的多种神经病理状况有关。有研究表明，NMDA 神经毒性具有发育调控性，但确切的调控模式存在争议，其潜在机制在很大程度上仍不清楚。在这里，我们发现 NMDA 处理会导致成熟（体外培养 9 天和 12 天）海马神经元或新生后 12 天和成年大鼠海马中的细胞死亡，但不会导致未成熟（体外培养 3 天和 6 天）神经元或胚胎 18 天和新生大鼠海马中的细胞死亡。相比之下，NMDA 促进未成熟神经元对抗营养剥夺的存活。有趣的是，研究发现 NMDA 优先激活成熟神经元和成年大鼠海马中的 p38 MAPK，但它有利于未成熟神经元和新生后 0 天大鼠海马中的 ERK1/2 激活。此外，研究表明成熟神经元中的 NMDA 神经毒性是通过 p38 MAPK 激活介导的，未成熟神经元中的神经保护是通过 ERK1/2 激活介导的，而所有这些效应都依赖于含有 NR2B 的 NMDAR，以及依赖于 Ca(2+)。我们还揭示了成熟和未成熟神经元在 NMDA 诱导的细胞内钙增加幅度上没有差异。然而，研究表明神经元成熟过程中细胞内钙基础水平升高，这种升高归因于 NMDA 神经毒性的变化，而不是 NMDAR 信号通路的转换。综上所述，我们的研究结果表明，NMDA 受体偏爱细胞内信号通路从 ERK1/2 向 p38 MAPK 的转换以及随年龄增长细胞内钙基础水平的升高可能是海马神经元中 NMDA 神经毒性发育变化的关键因素。
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