Department of Ophthalmology and BasicMedical Science, University of Missouri, Kansas City, MO 64108, USA.
Neuroscience. 2011 Feb 23;175:281-91. doi: 10.1016/j.neuroscience.2010.11.010. Epub 2010 Nov 11.
Dysregulation of Ca(2+) signaling following oxidative stress is an important pathophysiological mechanism of many chronic neurodegenerative disorders, including Alzheimer's disease, age-related macular degeneration, glaucomatous and diabetic retinopathies. However, the underlying mechanisms of disturbed intracellular Ca(2+) signaling remain largely unknown. We here describe a novel mechanism for increased intracellular Ca(2+) release following oxidative stress in a neuronal cell line. Using an experimental approach that included quantitative polymerase chain reaction, quantitative immunoblotting, microfluorimetry and the optical imaging of intracellular Ca(2+) release, we show that sub-lethal tert-butyl hydroperoxide-mediated oxidative stress result in a selective up-regulation of type-2 inositol-1,4,5,-trisphophate receptors. This oxidative stress mediated change was detected both at the transcriptional and translational level and functionally resulted in increased Ca(2+) release into the nucleoplasm from the membranes of the nuclear envelope at a given receptor-specific stimulus. Our data describe a novel source of Ca(2+) dysregulation induced by oxidative stress with potential relevance for differential subcellular Ca(2+) signaling specifically within the nucleus and the development of novel neuroprotective strategies in neurodegenerative disorders.
氧化应激后钙（Ca2+）信号的失调是许多慢性神经退行性疾病的重要病理生理机制，包括阿尔茨海默病、年龄相关性黄斑变性、青光眼和糖尿病性视网膜病变。然而，细胞内 Ca（Ca2+）信号紊乱的潜在机制在很大程度上仍不清楚。我们在这里描述了一种神经元细胞系在氧化应激后增加细胞内 Ca（Ca2+）释放的新机制。使用包括定量聚合酶链反应、定量免疫印迹、微荧光计和细胞内 Ca（Ca2+）释放的光学成像在内的实验方法，我们表明亚致死 tert-丁基过氧化物介导的氧化应激导致 2 型肌醇 1,4,5-三磷酸受体的选择性上调。这种氧化应激介导的变化在转录和翻译水平上均有检测到，并在功能上导致在特定受体特异性刺激下，从核膜进入核质的 Ca（Ca2+）释放增加。我们的数据描述了一种由氧化应激诱导的 Ca（Ca2+）调节异常的新来源，对于特定于核内的差异亚细胞 Ca（Ca2+）信号以及神经退行性疾病中新型神经保护策略的发展具有潜在相关性。
