Mechanisms of Oxidative Glutamate Toxicity: The Glutamate/Cystine Antiporter System xc- as a Neuroprotective Drug Target
Mechanisms of Oxidative Glutamate Toxicity: The Glutamate/Cystine Antiporter System xc- as a Neuroprotective Drug Target
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DOI：
10.2174/187152710791292567
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发表时间：
2010-07-01
影响因子：
3
通讯作者：
Methner, Axel
中科院分区：
文献类型：
--
作者：
Albrecht, Philipp;Lewerenz, Jan;Methner, Axel
谷氨酸/胱氨酸反向转运体系统x（c）（-）以1：1的比例将胱氨酸转运到细胞中，以交换重要的神经递质谷氨酸。它由通过二硫键连接的特异性轻链xCT和重链4F 2组成。这两种亚基主要定位于小鼠和人脑中，特别是在脑和外周之间的边界区域，包括血管内皮细胞、室管膜细胞、脉络丛和软脑膜。由系统x（c）（-）输出的谷氨酸主要负责脑中细胞外谷氨酸的浓度，而输入的胱氨酸则是合成主要的内源性抗氧化剂谷胱甘肽所必需的。系统x（c）（-）因此将抗氧化防御与神经传递和行为联系起来。系统x（c）（-）的功能紊乱与神经细胞死亡有关，这是由于细胞外谷氨酸盐增加和细胞内谷胱甘肽减少。在体外，通过系统x（c）（-）抑制胱氨酸输入导致细胞死亡，其机制称为氧化谷氨酸毒性或氧化作用，包括细胞内谷胱甘肽耗竭、12-脂氧合酶激活、细胞内过氧化物积累和环磷酸鸟苷（cGMP）依赖性钙通道激活，直至死亡级联反应结束。由氧化引起的细胞死亡不同于经典的细胞凋亡。在这篇文章中，我们讨论了系统x（c）（-）在体外和体内的功能，xCT作为一个重要的作用，但由于其双重作用可能是矛盾的药物靶点，和相关的氧化作为一种体外试验，用于识别新的神经保护蛋白和信号通路。
The glutamate/cystine antiporter system x(c)(-) transports cystine into cells in exchange for the important neurotransmitter glutamate at a ratio of 1:1. It is composed of a specific light chain, xCT, and a heavy chain, 4F2, linked by a disulfide bridge. Both subunits are localized prominently in the mouse and human brain especially in border areas between the brain and periphery including vascular endothelial cells, ependymal cells, choroid plexus, and leptomeninges. Glutamate exported by system x(c)(-) is largely responsible for the extracellular glutamate concentration in the brain, whereas the imported cystine is required for the synthesis of the major endogenous antioxidant, glutathione. System x(c)(-) thus connects the antioxidant defense with neurotransmission and behavior. Disturbances in the function of system x(c)(-) have been implicated in nerve cell death due to increased extracellular glutamate and reduced intracellular glutathione. In vitro, inhibition of cystine import through system x(c)(-) leads to cell death by a mechanism called oxidative glutamate toxicity or oxytosis, which includes depletion of intracellular glutathione, activation of 12-lipoxygenase, accumulation of intracellular peroxides, and the activation of a cyclic guanosine monophosphate (cGMP)-dependent calcium channel towards the end of the death cascade. Cell death caused by oxytosis is distinct from classical apoptosis. In this contribution, we discuss the function of system x(c)(-) in vitro and in vivo, the role of xCT as an important but due to its dual role probably ambivalent drug target, and the relevance of oxytosis as an in vitro assay for the identification of novel neuroprotective proteins and signaling pathways.