Laboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
J Neurosci. 2012 May 9;32(19):6642-50. doi: 10.1523/JNEUROSCI.6008-11.2012.
Glutamate excitotoxicity, a major component of many neurodegenerative disorders, is characterized by excessive calcium influx selectively through NMDARs. However, there is a substantial uncertainty concerning why other known routes of significant calcium entry, in particular, 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.
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，其特征是过量的钙内流选择性地通过 NMDA 受体。然而，人们对于为什么其他已知的大量钙进入途径，特别是 VGCCs，没有同样的毒性存在很大的不确定性。在这里，我们报告说，在大鼠海马和皮质培养物中的大多数神经元中，最大程度的 L 型 VGCC 激活引起的钙加载远低于毒性 NMDA 激活。因此，很少有去极化激活的神经元表现出钙失调和细胞死亡。钙进入的替代途径的激活与钙加载的程度成正比诱导神经元死亡。在一小部分神经元中，去极化引起更强的钙升高，接近由毒性 NMDA 引起的钙升高。这些神经元的特征是 VGCC 表达升高和增强的电压门控钙电流、线粒体功能障碍和细胞死亡。防止 VGCC 依赖性线粒体钙加载导致细胞质钙升高增强，而抑制线粒体钙清除则加速线粒体去极化。这两种观察结果都进一步表明线粒体功能障碍与 VGCC 介导的细胞死亡有关。结果表明，神经元的脆弱性与钙加载的程度有关，但似乎并不明确依赖于钙进入的途径。
