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

Andrew A. Pieper, Seth Blackshaw, Emily E. Clements, Daniel J. Brat, David K. Krug, Alison J. White, Patricia Pinto-Garcia, Antonella Favit, Jill R. Conover, Solomon H Snyder, Ajay Verma

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1845-1850
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number4
DOIs
StatePublished - Feb 15 2000

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DNA Breaks
Poly(ADP-ribose) Polymerases
Synaptic Transmission
Adenosine Diphosphate
Glutamic Acid
Nitric Oxide
Nitric Oxide Synthase Type I
NAD
N-Methylaspartate
Adenosine Diphosphate Ribose
Gene Deletion
Nuclear Proteins
N-Methyl-D-Aspartate Receptors
DNA Damage
Cause of Death
Skeletal Muscle
Cell Death
Spleen
Adenosine Triphosphate
Kidney

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Poly(ADP-ribosyl)ation basally activated by DNA strand breaks reflects glutamate-nitric oxide neurotransmission. / Pieper, Andrew A.; Blackshaw, Seth; Clements, Emily E.; Brat, Daniel J.; Krug, David K.; White, Alison J.; Pinto-Garcia, Patricia; Favit, Antonella; Conover, Jill R.; Snyder, Solomon H; Verma, Ajay.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 4, 15.02.2000, p. 1845-1850.

Research output: Contribution to journalArticle

Pieper, Andrew A. ; Blackshaw, Seth ; Clements, Emily E. ; Brat, Daniel J. ; Krug, David K. ; White, Alison J. ; Pinto-Garcia, Patricia ; Favit, Antonella ; Conover, Jill R. ; Snyder, Solomon H ; Verma, Ajay. / Poly(ADP-ribosyl)ation basally activated by DNA strand breaks reflects glutamate-nitric oxide neurotransmission. In: Proceedings of the National Academy of Sciences of the United States of America. 2000 ; Vol. 97, No. 4. pp. 1845-1850.
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