Fujikawa Denson G
David Geffen School of Medicine, University of California at Los Angeles, VA Greater Los Angeles Healthcare System, United States.
Comput Struct Biotechnol J. 2015 Mar 28;13:212-21. doi: 10.1016/j.csbj.2015.03.004. eCollection 2015.
Excitotoxicity involves the excessive release of glutamate from presynaptic nerve terminals and from reversal of astrocytic glutamate uptake, when there is excessive neuronal depolarization. N-methyl-d-aspartate (NMDA) receptors, a subtype of glutamate receptor, are activated in postsynaptic neurons, opening their receptor-operated cation channels to allow Ca(2 +) influx. The Ca(2 +) influx activates two enzymes, calpain I and neuronal nitric oxide synthase (nNOS). Calpain I activation produces mitochondrial release of cytochrome c (cyt c), truncated apoptosis-inducing factor (tAIF) and endonuclease G (endoG), the lysosomal release of cathepsins B and D and DNase II, and inactivation of the plasma membrane Na(+)-Ca(2 +) exchanger, which add to the buildup of intracellular Ca(2 +). tAIF is involved in large-scale DNA cleavage and cyt c may be involved in chromatin condensation; endoG produces internucleosomal DNA cleavage. The nuclear actions of the other proteins have not been determined. nNOS forms nitric oxide (NO), which reacts with superoxide (O2 (-)) to form peroxynitrite (ONOO(-)). These free radicals damage cellular membranes, intracellular proteins and DNA. DNA damage activates poly(ADP-ribose) polymerase-1 (PARP-1), which produces poly(ADP-ribose) (PAR) polymers that exit nuclei and translocate to mitochondrial membranes, also releasing AIF. Poly(ADP-ribose) glycohydrolase hydrolyzes PAR polymers into ADP-ribose molecules, which translocate to plasma membranes, activating melastatin-like transient receptor potential 2 (TRPM-2) channels, which open, allowing Ca(2 +) influx into neurons. NADPH oxidase (NOX1) transfers electrons across cellular membranes, producing O2 (-). The result of these processes is neuronal necrosis, which is a programmed cell death that is the basis of all acute neuronal injury in the adult brain.
兴奋性毒性涉及当神经元过度去极化时，突触前神经末梢谷氨酸的过度释放以及星形胶质细胞谷氨酸摄取的逆转。N-甲基-D-天冬氨酸（NMDA）受体是谷氨酸受体的一种亚型，在突触后神经元中被激活，打开其受体操纵的阳离子通道，使Ca(2+)内流。Ca(2+)内流激活两种酶，钙蛋白酶I和神经元型一氧化氮合酶（nNOS）。钙蛋白酶I的激活导致细胞色素c（cyt c）、截短的凋亡诱导因子（tAIF）和核酸内切酶G（endoG）从线粒体释放，组织蛋白酶B和D以及脱氧核糖核酸酶II从溶酶体释放，以及质膜Na(+)-Ca(2+)交换器失活，这些都增加了细胞内Ca(2+)的积累。tAIF参与大规模DNA切割，cyt c可能参与染色质凝聚；endoG产生核小体间DNA切割。其他蛋白质的核作用尚未确定。nNOS形成一氧化氮（NO），它与超氧阴离子（O2(-)）反应形成过氧亚硝酸盐（ONOO(-)）。这些自由基会损伤细胞膜、细胞内蛋白质和DNA。DNA损伤激活聚（ADP-核糖）聚合酶-1（PARP-1），它产生聚（ADP-核糖）（PAR）聚合物，这些聚合物离开细胞核并转移到线粒体膜上，同时也释放AIF。聚（ADP-核糖）糖苷水解酶将PAR聚合物水解成ADP-核糖分子，这些分子转移到质膜上，激活褪黑素样瞬时受体电位2（TRPM-2）通道，通道打开，使Ca(2+)流入神经元。NADPH氧化酶（NOX1）跨细胞膜传递电子，产生O2(-)。这些过程的结果是神经元坏死，这是一种程序性细胞死亡，是成人大脑所有急性神经元损伤的基础。
