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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Poly(ADP-ribosyl)ation basally activated by DNA strand breaks reflects glutamate--nitric oxide neurotransmission
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Poly(ADP-ribosyl)ation basally activated by DNA strand breaks reflects glutamate--nitric oxide neurotransmission

机译：DNA链断裂基本激活的聚（ADP-核糖基）化反应反映了谷氨酸-一氧化氮的神经传递

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摘要

Poly(ADP-ribose) polymerase (PARP) transfers ADP ribose groups from NAD+ to nuclear proteins after activation by DNA strand breaks. PARP overactivation by massive DNA damage causes cell death via NAD+ and ATP depletion. Heretofore, PARP has been thought to be inactive under basal physiologic conditions. We now report high basal levels of PARP activity and DNA strand breaks in discrete neuronal populations of the brain. in ventricular ependy- mal and subependymal cells and in peripheral tissues. In some peripheral tissues, such as skeletal muscle, spleen. heart. and kidney, PARP activity is reduced only partially in mice with PARP-1 gene deletion (PARP-1 --/--). implicating activity of alternative forms of PARP. Glutamate neurotransmission involving Nmethyl-D-as- partate (NMDA) receptors and neuronal nitric oxide synthase (nNOS) activity in part mediates neuronal DNA strand breaks and PARP activity, which are diminished by NMDA antagonists and NOS inhibitors and also diminished in mice with targeted deletion of nNOS gene (nNOS--/--). An increase in NAD+ levels after treatment with NMDA antagonists or NOS inhibitors, as well as in nNOS--/- mice, indicates that basal glutamate-PARP activity regulates neu- ronal energy dynamics.
机译：通过DNA链断裂激活后，聚（ADP-核糖）聚合酶（PARP）将ADP核糖基团从NAD +转移到核蛋白。大量DNA损伤导致PARP过度活化，导致细胞通过NAD +和ATP消耗而死亡。迄今为止，人们认为PARP在基础生理条件下是无活性的。现在，我们报告了大脑的离散神经元群体中PARP活性和DNA链断裂的高基础水平。在室上皮和室管膜下细胞以及周围组织中。在某些外周组织中，如骨骼肌，脾脏。心。在PARP-1基因缺失的小鼠（PARP-1-/-）中，PARP活性仅部分降低。暗示其他形式的PARP的活动。谷氨酸神经传递涉及N-甲基-天冬氨酸（NMDA）受体和神经元一氧化氮合酶（nNOS）活性，部分介导神经元DNA链断裂和PARP活性，这被NMDA拮抗剂和NOS抑制剂减弱，并且在有针对性的小鼠中也减弱删除nNOS基因（nNOS-/-）。用NMDA拮抗剂或NOS抑制剂以及nNOS-/-小鼠治疗后，NAD +水平升高，表明基础谷氨酸-PARP活性调节神经元能量动态。

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