Bossy-Wetzel Ella, Talantova Maria V, Lee Wilson D, Schölzke Marion N, Harrop Anne, Mathews Emily, Götz Thomas, Han Jiahuai, Ellisman Mark H, Perkins Guy A, Lipton Stuart A
Center for Neuroscience & Aging, The Burnham Institute, La Jolla, CA 92037, USA.
Neuron. 2004 Feb 5;41(3):351-65. doi: 10.1016/s0896-6273(04)00015-7.
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-xL, 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.
一氧化氮（NO）和锌（Zn2+）与脑缺血和神经退行性疾病的发病机制有关。然而，它们之间的关系以及神经毒性作用的分子机制仍不清楚。在此我们表明，添加外源性NO或NMDA（以增加内源性NO）会导致过氧亚硝酸根（ONOO-）形成，并随之使Zn2+从大脑皮质神经元的细胞内储存中释放出来。游离的Zn2+进而诱导呼吸阻滞、线粒体通透性转换（mPT）、细胞色素c释放、活性氧（ROS）生成以及p38丝裂原活化蛋白激酶激活。该途径导致不依赖半胱天冬酶的K+外流，伴有细胞体积减小和类凋亡死亡。此外，Zn2+螯合剂、ROS清除剂、Bcl-xL、显性干扰性p38或K+通道阻滞剂均能减弱NO诱导的K+外流、细胞体积减小和神经元凋亡。因此，这些数据确立了NO与Zn2+凋亡信号转导途径之间一种新的相互作用形式，这可能与神经退行性变有关。
