Comparative impact of voltage-gated calcium channels and NMDA receptors on mitochondria-mediated neuronal injury.
Comparative impact of voltage-gated calcium channels and NMDA receptors on mitochondria-mediated neuronal injury.
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DOI：
10.1523/jneurosci.6008-11.2012
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发表时间：
2012-05-09
期刊：
影响因子：
--
通讯作者：
Pivovarova NB
中科院分区：
文献类型：
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作者：
Stanika RI;Villanueva I;Kazanina G;Andrews SB;Pivovarova NB
谷氨酸兴奋性毒性是许多神经退行性疾病的主要组成部分，其特征在于选择性地通过NMDA受体（NMDAR）的过量钙内流。然而，关于为什么其他已知的重要钙进入途径，特别是电压门控钙通道（VGCC）没有类似的毒性，存在很大的不确定性。在这里，我们报告说，在大多数的大鼠海马和皮层培养的神经元，最大的L型VGCC激活诱导低得多的钙负荷比有毒的NMDAR激活。因此，少数去极化激活的神经元表现出钙失调和细胞死亡。钙离子进入的替代途径的激活诱导神经元死亡的程度成比例的钙负荷。在一小部分神经元中，去极化诱发了更强的钙离子升高，接近毒性NMDA诱导的钙离子升高。这些神经元的特征是VGCC表达升高，电压门控钙电流增强，线粒体功能障碍和细胞死亡。阻止VGCC依赖的线粒体钙负荷导致更强的细胞质钙升高，而抑制线粒体钙清除加速线粒体去极化。这两个观察结果进一步暗示VGCC介导的细胞死亡中的线粒体功能障碍。结果表明，神经元的脆弱性跟踪钙负荷的程度，但似乎并不明确依赖于钙进入的途径。
Glutamate excitotoxicity, a major component of many neurodegenerative disorders, is characterized by excessive calcium influx selectively through NMDA receptors (NMDARs). However, there is a substantial uncertainty concerning why other known routes of significant calcium entry, in particular voltage-gated calcium channels (VGCCs), are not similarly toxic. Here, we report that in the majority of neurons in rat hippocampal and cortical cultures, maximal L-type VGCC activation induces much lower calcium loading than toxic NMDAR activation. Consequently, few depolarization-activated neurons exhibit calcium deregulation and cell death. Activation of alternative routes of calcium entry induced neuronal death in proportion to the degree of calcium loading. In a small subset of neurons depolarization evoked stronger calcium elevations, approaching those induced by toxic NMDA. These neurons were characterized by elevated expression of VGCCs and enhanced voltage-gated calcium currents, mitochondrial dysfunction and cell death. Preventing VGCC-dependent mitochondrial calcium loading resulted in stronger cytoplasmic calcium elevations, whereas inhibiting mitochondrial calcium clearance accelerated mitochondrial depolarization. Both observations further implicate mitochondrial dysfunction in VGCC-mediated cell death. Results indicate that neuronal vulnerability tracks the extent of calcium loading but does not appear to depend explicitly on the route of calcium entry.