Microglia induce neurotoxicity Zn2+ release and a K+ current via intraneuronal surge
Microglia induce neurotoxicity Zn2+ release and a K+ current via intraneuronal surge
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DOI：
10.1002/glia.20592
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发表时间：
2008-01-01
期刊：
影响因子：
6.2
通讯作者：
Aizenman, Elias
中科院分区：
文献类型：
--
作者：
Knoch, Megan E.;Hartnett, Karen A.;Aizenman, Elias
小胶质细胞是许多神经退行性疾病中损伤级联反应的关键组成部分。然而，小胶质细胞介导神经元细胞死亡的确切分子机制尚未完全阐明。我们在这里报告说，活性物种从激活的小胶质细胞释放诱导锌2+从细胞内存储在培养的皮层神经元，随后增强神经元电压门控K+电流，两个事件，已密切相关的细胞凋亡。NADPH氧化酶抑制剂apocynin、超氧化物歧化酶和过氧化氢酶的自由基清除混合物以及5，10，15，20-四（4-sulfonatophenyl）porphyrinato氯化铁（III）均能阻止神经元内Zn ~（2+）释放和K ~+电流浪涌。通过神经元过表达金属硫蛋白III或通过表达上游丝裂原活化蛋白激酶凋亡信号调节激酶-1（ASK-1）的显性负性（DN）载体来防止K+电流的增强。重要的是，过表达金属硫蛋白-III或转染有ASK-1或Kv2.1编码的K+通道的DN载体的神经元对小胶质细胞诱导的毒性具有抗性。这些结果建立了小胶质细胞产生的氧和氮反应产物和细胞内锌释放介导的神经细胞死亡和K+电流激增之间的直接联系。(c)2007 Wiley-Liss，Inc.
Microglial cells are critical components of the injurious cascade in a large number of neurodegenerative diseases. However, the precise molecular mechanisms by which microglia mediate neuronal cell death have not been fully delineated. We report here that reactive species released from activated microglia induce the liberation of Zn2+ from intracellular stores in cultured cortical neurons, with a subsequent enhancement in neuronal voltage-gated K+ currents, two events that have been intimately linked to apoptosis. Both the intraneuronal Zn2+ release and the K+ current surge could be prevented by the NADPH oxidase inhibitor apocynin, the free radical scavenging mixture of superoxide dismutase and catalase, as well as by 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride. The enhancement of K+ currents was prevented by neuronal overexpression of metallothionein III or by expression of a dominant negative (DN) vector for the upstream mitogen-activated protein kinase apoptosis signal regulating kinase-1 (ASK-1). Importantly, neurons overexpressing metallothionein-Ill or transfected with DN vectors for ASK-1 or Kv2.1-encoded K+ channels were resistant to microglial-induced toxicity. These results establish a direct link between microglial-generated oxygen and nitrogen reactive products and neuronal cell death mediated by intracellular Zn2+ release and a surge in K+ currents. (c) 2007 Wiley-Liss, Inc.