Pieper A A, Blackshaw S, Clements E E, Brat D J, Krug D K, White A J, Pinto-Garcia P, Favit A, Conover J R, Snyder S H, Verma A
Departments of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1845-50. doi: 10.1073/pnas.97.4.1845.
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 ependymal 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 N-methyl-d-aspartate (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 neuronal energy dynamics.
聚（ADP - 核糖）聚合酶（PARP）在被DNA链断裂激活后，将ADP核糖基团从NAD（+）转移至核蛋白。大量DNA损伤导致的PARP过度激活会通过消耗NAD（+）和ATP引起细胞死亡。迄今为止，PARP一直被认为在基础生理条件下是无活性的。我们现在报告，在大脑离散的神经元群体、脑室室管膜和室管膜下细胞以及外周组织中，PARP活性和DNA链断裂处于较高的基础水平。在一些外周组织，如骨骼肌、脾脏、心脏和肾脏中，PARP - 1基因缺失的小鼠（PARP - 1（- / -））的PARP活性仅部分降低，这表明存在其他形式的PARP活性。涉及N - 甲基 - D - 天冬氨酸（NMDA）受体的谷氨酸能神经传递和神经元一氧化氮合酶（nNOS）活性部分介导了神经元DNA链断裂和PARP活性，NMDA拮抗剂和NOS抑制剂可使其降低，在nNOS基因靶向缺失的小鼠（nNOS（- / -））中也降低。用NMDA拮抗剂或NOS抑制剂处理后以及在nNOS（- / -）小鼠中NAD（+）水平升高，表明基础谷氨酸 - PARP活性调节神经元能量动态。
