He Jie, Kang Hongjun, Yan Fang, Chen Chang
Center for Molecular Biology, Institute of Biophysics, Chinese Academy of Sciences, P.O. Box 33, 15 Datun Road, Chaoyang District, Beijing 100101, PR China.
Brain Res. 2004 Jul 23;1015(1-2):25-33. doi: 10.1016/j.brainres.2004.04.022.
Nitric oxide (NO)-induced neurotoxicities are involved in the pathogenesis of several neurodegenerative disorders featured by misfolded proteins. However, the details remain to be investigated. In the present work, we focus on the study of some endoplasmic reticulum-related events in S-nitrosoglutathione (GSNO)-induced neurotoxicity in cerebellar granule cells (CGCs) and we demonstrated that: (1) GSNO caused sustained elevation of intracellular calcium; (2) This calcium elevation resulted partially from the depletion of endoplasmic reticulum (ER) calcium stores; (3) There was ER stress which was indicated by the incomplete splicing of X-box binding protein (XBP-1) mRNA by 8-polysialyltransferase (Pst1); (4) GSNO upregulated the expression of the proapoptotic growth arrest and DNA damage-inducible gene (Gadd153) and caused the depletion of intracellular glutathione (GSH) pools. At the same time, GSNO downregulated the expression of the antiapoptotic gene Sarco/endoplasmic reticulum calcium-ATPase (SERCA2b) in parallel with the downregulation of the antiapoptotic ER chaperones-glucose-regulated protein genes (Grp78 and Grp94). These effects indicate that ER is one of the NO targets in GSNO-induced neurotoxicity in cerebellar granule cells besides mitochondria.
一氧化氮（NO）诱导的神经毒性参与了几种以蛋白质错误折叠为特征的神经退行性疾病的发病机制。然而，具体细节仍有待研究。在本研究中，我们聚焦于小脑颗粒细胞（CGC）中S-亚硝基谷胱甘肽（GSNO）诱导的神经毒性中一些内质网相关事件的研究，并且我们证明：（1）GSNO导致细胞内钙持续升高；（2）这种钙升高部分源于内质网（ER）钙储备的耗竭；（3）存在内质网应激，这通过8-聚唾液酸转移酶（Pst1）对X盒结合蛋白（XBP-1）mRNA的不完全剪接来指示；（4）GSNO上调促凋亡的生长停滞和DNA损伤诱导基因（Gadd153）的表达并导致细胞内谷胱甘肽（GSH）池的耗竭。同时，GSNO下调抗凋亡基因肌浆/内质网钙ATP酶（SERCA2b）的表达，同时下调抗凋亡内质网伴侣蛋白——葡萄糖调节蛋白基因（Grp78和Grp94）。这些效应表明，除线粒体之外，内质网是GSNO诱导的小脑颗粒细胞神经毒性中的NO作用靶点之一。
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