Sensi S L, Jeng J-M
Department of Neurology, University of California, Irvine. Irvine, CA 92697-4292, USA.
Curr Mol Med. 2004 Mar;4(2):87-111. doi: 10.2174/1566524043479211.
Zn(2+) plays an important role in diverse physiological processes, but when released in excess amounts it is potently neurotoxic. In vivo trans-synaptic movement and subsequent post-synaptic accumulation of intracellular Zn(2+) contributes to the neuronal injury observed in some forms of cerebral ischemia. Zn(2+) may enter neurons through NMDA channels, voltage-sensitive calcium channels, Ca(2+)-permeable AMPA/kainate (Ca-A/K) channels, or Zn(2+)-sensitive membrane transporters. Furthermore, Zn(2+) is also released from intracellular sites such as metallothioneins and mitochondria. The mechanisms by which Zn(2+) exerts its potent neurotoxic effects involve many signaling pathways, including mitochondrial and extra-mitochondrial generation of reactive oxygen species (ROS) and disruption of metabolic enzyme activity, ultimately leading to activation of apoptotic and/or necrotic processes. As is the case with Ca(2+), neuronal mitochondria take up Zn(2+) as a way of modulating cellular Zn(2+) homeostasis. However, excessive mitochondrial Zn(2+) sequestration leads to a marked dysfunction of these organelles, characterized by prolonged ROS generation. Intriguingly, in direct comparison to Ca(2+), Zn(2+) appears to induce these changes with a considerably greater degree of potency. These effects are particularly evident upon large (i.e., micromolar) rises in intracellular Zn(2+) concentration (Zn(2+)), and likely hasten necrotic neuronal death. In contrast, sub-micromolar Zn(2+) increases promote release of pro-apoptotic factors, suggesting that different intensities of Zn(2+) load may activate distinct pathways of injury. Finally, Zn(2+) homeostasis seems particularly sensitive to the environmental changes observed in ischemia, such as acidosis and oxidative stress, indicating that alterations in Zn(2+) may play a very significant role in the development of ischemic neuronal damage.
锌离子（Zn(2+)）在多种生理过程中发挥着重要作用，但当过量释放时，它具有很强的神经毒性。体内细胞内锌离子的跨突触移动及随后在突触后的积累，会导致在某些形式的脑缺血中观察到的神经元损伤。锌离子可能通过N-甲基-D-天冬氨酸（NMDA）通道、电压敏感性钙通道、钙通透型α-氨基-3-羟基-5-甲基-4-异恶唑丙酸/海人藻酸（Ca-A/K）通道或锌离子敏感膜转运体进入神经元。此外，锌离子还从细胞内位点如金属硫蛋白和线粒体中释放出来。锌离子发挥其强大神经毒性作用的机制涉及许多信号通路，包括线粒体和线粒体外活性氧（ROS）的产生以及代谢酶活性的破坏，最终导致凋亡和/或坏死过程的激活。与钙离子（Ca(2+)）的情况一样，神经元线粒体摄取锌离子作为调节细胞内锌离子稳态的一种方式。然而，线粒体对锌离子的过度螯合会导致这些细胞器明显功能障碍，其特征是ROS生成延长。有趣的是，与钙离子直接相比，锌离子似乎能以相当大的效力诱导这些变化。当细胞内锌离子浓度（Zn(2+)）大幅升高（即微摩尔级）时，这些效应尤为明显，并可能加速坏死性神经元死亡。相比之下，亚微摩尔级的Zn(2+)升高会促进促凋亡因子的释放，这表明不同强度的Zn(2+)负荷可能激活不同的损伤途径。最后，锌离子稳态似乎对缺血时观察到的环境变化（如酸中毒和氧化应激）特别敏感，这表明Zn(2+)的改变可能在缺血性神经元损伤的发展中起非常重要的作用。
