Bonfoco E, Leist M, Zhivotovsky B, Orrenius S, Lipton S A, Nicotera P
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
J Neurochem. 1996 Dec;67(6):2484-93. doi: 10.1046/j.1471-4159.1996.67062484.x.
We have recently demonstrated that nitric oxide (NO) donors can trigger either apoptosis or necrosis of neurons as a function of the intensity of the exposure. Here, we show that the apoptosis induced by the NO donors S-nitrosocysteine (SNOC) or S-nitroso-N-acetyl-penicillamine (SNAP) in cultured cerebellar granule cells (CGCs) depends on NMDA receptor (NMDA-R) activation leading to intracellular Ca2+ overload. Early dissolution of actin filaments followed by breakdown of microtubules and nuclear lamins preceded the appearance of typical apoptotic features. NO donors induced tyrosine nitration in neurons, in a small population of contaminating astrocytes, and in cultures of cerebellar astroglial cells. However, astrocytes neither displayed cytoskeletal alterations nor underwent apoptosis. Competitive and uncompetitive NMDA receptor antagonists, such as D-aminophosphonovaleric acid and MK-801, did not influence tyrosine nitration but prevented the accumulation of intracellular Ca2+, cytoskeletal breakdown, and apoptosis induced by either SNOC or SNAP in CGCs. Taken together, these data strongly suggest that Ca2+ influx through NMDA-R-gated ion channels is a critical event in CGC apoptosis induced by NO donors.
我们最近证明，一氧化氮（NO）供体可根据暴露强度触发神经元凋亡或坏死。在此，我们表明，NO供体S-亚硝基半胱氨酸（SNOC）或S-亚硝基-N-乙酰青霉胺（SNAP）在培养的小脑颗粒细胞（CGC）中诱导的凋亡取决于NMDA受体（NMDA-R）激活，导致细胞内Ca2+过载。典型凋亡特征出现之前，肌动蛋白丝早期溶解，随后微管和核纤层分解。NO供体在神经元、一小部分污染的星形胶质细胞以及小脑星形胶质细胞培养物中诱导酪氨酸硝化。然而，星形胶质细胞既未显示细胞骨架改变，也未发生凋亡。竞争性和非竞争性NMDA受体拮抗剂，如D-氨基磷酸戊酸和MK-801，不影响酪氨酸硝化，但可防止CGC中细胞内Ca2+积累、细胞骨架分解以及由SNOC或SNAP诱导的凋亡。综上所述，这些数据强烈表明，通过NMDA-R门控离子通道的Ca2+内流是NO供体诱导CGC凋亡的关键事件。
