Jimenez-Blasco D, Santofimia-Castaño P, Gonzalez A, Almeida A, Bolaños J P
Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, 37007 Salamanca, Spain.
Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, 37007 Salamanca, Spain.
Cell Death Differ. 2015 Nov;22(11):1877-89. doi: 10.1038/cdd.2015.49. Epub 2015 Apr 24.
Neurotransmission unavoidably increases mitochondrial reactive oxygen species. However, the intrinsic antioxidant defense of neurons is weak and hence the mechanism whereby these cells are physiologically protected against oxidative damage is unknown. Here we found that the antioxidant defense of neurons is repressed owing to the continuous protein destabilization of the master antioxidant transcriptional activator, nuclear factor-erythroid 2-related factor-2 (Nrf2). By contrast, Nrf2 is highly stable in neighbor astrocytes explaining their robust antioxidant defense and resistance against oxidative stress. We also show that subtle and persistent stimulation of N-methyl-d-aspartate receptors (NMDAR) in astrocytes, through a mechanism not requiring extracellular Ca²⁺ influx, upregulates a signal transduction pathway involving phospholipase C-mediated endoplasmic reticulum release of Ca²⁺ and protein kinase Cδ activation. Active protein kinase Cδ promotes, by phosphorylation, the stabilization of p35, a cyclin-dependent kinase-5 (Cdk5) cofactor. Active p35/Cdk5 complex in the cytosol phosphorylates Nrf2 at Thr(395), Ser(433) and Thr(439) that is sufficient to promote Nrf2 translocation to the nucleus and induce the expression of antioxidant genes. Furthermore, this Cdk5-Nrf2 transduction pathway boosts glutathione metabolism in astrocytes efficiently protecting closely spaced neurons against oxidative damage. Thus, intercellular communication through NMDAR couples neurotransmission with neuronal survival.
神经传递不可避免地会增加线粒体活性氧。然而，神经元的内在抗氧化防御能力较弱，因此这些细胞在生理上免受氧化损伤的机制尚不清楚。在这里，我们发现神经元的抗氧化防御因主要抗氧化转录激活因子核因子红系2相关因子2（Nrf2）的持续蛋白质不稳定而受到抑制。相比之下，Nrf2在邻近的星形胶质细胞中高度稳定，这解释了它们强大的抗氧化防御能力和对氧化应激的抵抗力。我们还表明，通过一种不需要细胞外Ca²⁺内流的机制，对星形胶质细胞中的N-甲基-D-天冬氨酸受体（NMDAR）进行微妙而持续的刺激，会上调一条信号转导通路，该通路涉及磷脂酶C介导的内质网Ca²⁺释放和蛋白激酶Cδ激活。活性蛋白激酶Cδ通过磷酸化促进细胞周期蛋白依赖性激酶5（Cdk5）辅因子p35的稳定。胞质溶胶中的活性p35/Cdk5复合物在Thr(395)、Ser(433)和Thr(439)位点磷酸化Nrf2，这足以促进Nrf2易位至细胞核并诱导抗氧化基因的表达。此外，这条Cdk5-Nrf2转导通路增强了星形胶质细胞中的谷胱甘肽代谢，有效保护相邻的神经元免受氧化损伤。因此，通过NMDAR的细胞间通讯将神经传递与神经元存活联系起来。
