Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels
Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels
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DOI：
10.1016/s0896-6273(04)00015-7
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发表时间：
2004-02-05
期刊：
影响因子：
16.2
通讯作者：
Lipton, SA
中科院分区：
文献类型：
--
作者：
Bossy-Wetzel, E;Talantova, MV;Lipton, SA
一氧化氮（NO）和锌（Zn 2+）参与脑缺血和神经退行性疾病的发病机制。然而，它们之间的关系及其神经毒性作用的分子机制仍不清楚。在这里，我们表明，除了外源性NO或NMDA（增加内源性NO）导致过氧亚硝酸盐（ONOO-）的形成和随后的锌2+释放从细胞内存储在皮层神经元。游离Zn 2+依次诱导呼吸阻滞、线粒体通透性转换（mPT）、细胞色素c释放、活性氧（ROS）的产生和p38 MAP激酶活化。该途径导致非半胱天冬酶依赖性K+流出，伴随细胞体积损失和类凋亡性死亡。此外，Zn 2+螯合剂、ROS清除剂、Bcl-x（L）、显性干扰p38或K+通道阻断剂均减弱NO诱导的K+流出、细胞体积损失和神经元凋亡。因此，这些数据建立了一种新的形式的串扰之间的NO和Zn 2+凋亡信号转导途径，可能有助于神经变性。
Nitric oxide (NO) and zinc (Zn2+) are implicated in the pathogenesis of cerebral ischemia and neurodegenerative diseases. However, their relationship and the molecular mechanism of their neurotoxic effects remain unclear. Here we show that addition of exogenous NO or NMDA (to increase endogenous NO) leads to peroxynitrite (ONOO-) formation and consequent Zn2+ release from intracellular stores in cerebrocortical neurons. Free Zn2+ in turn induces respiratory block, mitochondrial permeability transition (mPT), cytochrome c release, generation of reactive oxygen species (ROS), and p38 MAP kinase activation. This pathway leads to caspase-independent K+ efflux with cell volume loss and apoptotic-like death. Moreover, Zn2+ chelators, ROS scavengers, Bcl-x(L), dominant-interfering p38, or K+ channel blockers all attenuate NO-induced K+ efflux, cell volume loss, and neuronal apoptosis. Thus, these data establish a new form of crosstalk between NO and Zn2+ apoptotic signal transduction pathways that may contribute to neurodegeneration.