Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicity
Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicity
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DOI：
10.1073/pnas.0903546106
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发表时间：
2009-06-16
影响因子：
11.1
通讯作者：
Andrews, S. Brian
中科院分区：
文献类型：
--
作者：
Stanika, Ruslan I.;Pivovarova, Natalia B.;Andrews, S. Brian
N-甲基-D-天冬氨酸受体(NMDAR)的过度激活是谷氨酸诱导的中枢神经元兴奋性毒性损伤的关键早期步骤。例如，受体位置或亚单位组成所指定的不同的NMDAR偶联通路似乎控制着谷氨酸诱导的兴奋性毒性死亡，但对于途径选择的潜在机制仍有许多不确定性。在这里，我们问是否以及如果是的话，特定于路线的脆弱性是否与钙超载和线粒体功能障碍相关联，这也是已知的兴奋毒性损伤的核心组成部分。在培养的海马神经元中，只有突触外NMDAR的过度激活才会导致钙离子内流到足以促进钙超载的程度，从而导致线粒体功能障碍和细胞死亡。受体组成本身似乎不是指定信号耦合的主要因素，因为抑制NR2B可以消除钙负载，并且只在主要表达NR2B的年轻神经元中起保护作用。在表达类似水平的NR2A和NR2B的NMDAR的老年神经元中，改善钙超载需要抑制包含这两个NR2亚单位的突触外受体。存活前的突触刺激也通过含有N2A和NR2B的NMDAR诱导钙内流，但与突触外NMDAR的兴奋毒性激活相反，只产生低幅度的细胞质钙尖峰和适度的、无害的线粒体钙积累。结果表明，兴奋性毒性钙离子进入的不同途径汇聚在一条共同的途径上，涉及钙超载导致的线粒体功能障碍--协调和统一了兴奋性毒性损伤的“特定路径”和“钙负荷依赖”观点的许多方面。
Overactivation of NMDA receptors (NMDARs) is a critical early step in glutamate-evoked excitotoxic injury of CNS neurons. Distinct NMDAR-coupled pathways specified by, for example, receptor location or subunit composition seem to govern glutamate-induced excitotoxic death, but there is much uncertainty concerning the underlying mechanisms of pathway selection. Here we ask whether, and if so how, route-specific vulnerability is coupled to Ca2+ overload and mitochondrial dysfunction, which is also a known, central component of exitotoxic injury. In cultured hippocampal neurons, over-activation of only extrasynaptic NMDARs resulted in Ca2+ entry strong enough to promote Ca2+ overload, which subsequently leads to mitochondrial dysfunction and cell death. Receptor composition per se appears not to be a primary factor for specifying signal coupling, as NR2B inhibition abolished Ca2+ loading and was protective only in predominantly NR2B-expressing young neurons. In older neurons expressing comparable levels of NR2A- and NR2B-containing NMDARs, amelioration of Ca2+ overload required the inhibition of extrasynaptic receptors containing both NR2 subunits. Prosurvival synaptic stimuli also evoked Ca2+ entry through both N2A- and NR2B-containing NMDARs, but, in contrast to excitotoxic activation of extrasynaptic NMDARs, produced only low-amplitude cytoplasmic Ca2+ spikes and modest, nondamaging mitochondrial Ca2+ accumulation. The results-showing that the various routes of excitotoxic Ca2+ entry converge on a common pathway involving Ca2+ overload-induced mitochondrial dysfunction-reconcile and unify many aspects of the "route-specific'' and "calcium load-dependent'' views of exitotoxic injury.