Poly(ADP-ribosyl)ation basally activated by DNA strand breaks reflects glutamate-nitric oxide neurotransmission

Poly(ADP-ribose) polymerase (PARP) transfers ADP ribose groups from NAD(+) to nuclear proteins after activation by DNA strand breaks. PARP overactivat ion by massive DNA damage causes cell death via NAD(+) and ATP depletion. H eretofore, PARP has been thought to be inactive under basal physiologic con ditions. We now report high basal levels of PARP activity and DNA strand br eaks in discrete neuronal populations of the brain, in ventricular ependyma l and subependymal cells and in peripheral tissues, In some peripheral tiss ues, such as skeletal muscle, spleen, heart, and kidney, PARP activity is r educed only partially in mice with PARP-1 gene deletion (PARP-1(-/-)). impl icating activity of alternative forms of PARP, Glutamate neurotransmission involving N-methyl-D-aspartate (NMDA) receptors and neuronal nitric oxide s ynthase (nNOS) activity in part mediates neuronal DNA strand breaks and PAR P activity, which are diminished by NMDA antagonists and NOS inhibitors and also diminished in mice with targeted deletion of nNOS gene (nNOS(-/-)). A n increase in NAD(+) levels after treatment with NMDA antagonists or NOS in hibitors, as well as in nNOS(-/-) mice, indicates that basal glutamate-PARP activity regulates neuronal energy dynamics.