The endoplasmic reticulum-related events in S-nitrosoglutathione-induced neurotoxicity in cerebellar granule cells
The endoplasmic reticulum-related events in S-nitrosoglutathione-induced neurotoxicity in cerebellar granule cells
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DOI：
10.1016/j.brainres.2004.04.022
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发表时间：
2004-07-23
期刊：
影响因子：
2.9
通讯作者：
Chen, C
中科院分区：
文献类型：
--
作者：
He, J;Kang, HJ;Chen, C
一氧化氮 (NO) 诱导的神经毒性参与了多种以错误折叠蛋白为特征的神经退行性疾病的发病机制。但具体细节仍有待调查。在本工作中，我们重点研究了S-亚硝基谷胱甘肽（GSNO）诱导的小脑颗粒细胞（CGC）神经毒性中的一些内质网相关事件，并证明：（1）GSNO引起细胞内钙持续升高； (2) 这种钙升高部分是由于内质网 (ER) 钙储备的耗尽所致； (3)存在内质网应激，表现为8-聚唾液酸转移酶(Pst1)对X-box结合蛋白(XBP-1)mRNA的不完全剪接； (4) GSNO 上调促凋亡生长停滞和 DNA 损伤诱导基因 (Gadd153) 的表达，并导致细胞内谷胱甘肽 (GSH) 库的耗尽。与此同时，GSNO 下调抗凋亡基因 Sarco/内质网钙-ATP 酶 (SERCA2b) 的表达，同时下调抗凋亡 ER 伴侣葡萄糖调节蛋白基因 (Grp78 和 Grp94)。这些效应表明，除了线粒体之外，ER 是 GSNO 诱导的小脑颗粒细胞神经毒性的 NO 靶标之一。 (C) 2004 Elsevier B.V. 保留所有权利。
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. (C) 2004 Elsevier B.V. All rights reserved.