Center for Neuroscience, Aging and Stem Cell Research, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell Calcium. 2010 Feb;47(2):190-7. doi: 10.1016/j.ceca.2009.12.009. Epub 2010 Jan 8.
Overactivation of the NMDA-subtype of glutamate receptor is known to trigger excessive calcium influx, contributing to neurodegenerative conditions. Such dysregulation of calcium signaling results in generation of excessive free radicals, including reactive oxygen and nitrogen species (ROS/RNS), including nitric oxide (NO). In turn, we and our colleagues have shown that these free radicals trigger pathological production of misfolded proteins, mitochondrial dysfunction, and apoptotic pathways in neuronal cells. Here, we discuss emerging evidence that excessive calcium-induced NO production can contribute to the accumulation of misfolded proteins, specifically by S-nitrosylation of the ubiquitin E3 ligase, parkin, and the chaperone enzyme for nascent protein folding, protein-disulfide isomerase. Additionally, excessive calcium-induced NO generation leads to the formation of S-nitrosylated dynamin-related protein 1, which causes abnormal mitochondrial fragmentation and resultant synaptic damage. In this review, we also discuss how two novel classes of pharmacological agents hold promise to interrupt these pathological processes. Firstly, the NMDA receptor antagonists, Memantine and NitroMemantine, block excessive extrasynaptic glutamate excitation while maintaining synaptic transmission, thereby limiting excessive calcium influx and production of ROS/RNS. Secondly, therapeutic pro-electrophiles are activated in the face of oxidative insult, thus protecting cells from calcium-induced oxidative stress via the Keap1/Nrf2 transcriptional pathway.
NMDA 型谷氨酸受体的过度激活已知会引发过多的钙内流，导致神经退行性疾病。钙信号的这种失调会导致过多的自由基产生，包括活性氧和氮物种 (ROS/RNS)，包括一氧化氮 (NO)。反过来，我们和我们的同事已经表明，这些自由基会触发神经元细胞中错误折叠蛋白质的病理性产生、线粒体功能障碍和细胞凋亡途径。在这里，我们讨论了新出现的证据，即过量钙诱导的 NO 产生可导致错误折叠蛋白质的积累，特别是通过泛素 E3 连接酶 parkin 和新生蛋白折叠伴侣蛋白二硫键异构酶的 S-亚硝基化。此外，过量钙诱导的 NO 生成导致 S-亚硝基化的与动力蛋白相关的蛋白 1 的形成，从而导致异常的线粒体片段化和随后的突触损伤。在这篇综述中，我们还讨论了两类新型药理学药物如何有希望中断这些病理过程。首先，NMDA 受体拮抗剂美金刚和硝普美金刚阻断过多的突触外谷氨酸兴奋，同时保持突触传递，从而限制过多的钙内流和 ROS/RNS 的产生。其次，治疗性亲电试剂在氧化应激下被激活，从而通过 Keap1/Nrf2 转录途径保护细胞免受钙诱导的氧化应激。
