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Molecular Pharmacology

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Research ArticleArticle

Regulation of Mitochondrial Poly(ADP-Ribose) Polymerase Activation by the β-Adrenoceptor/cAMP/Protein Kinase A Axis during Oxidative Stress

Attila Brunyanszki, Gabor Olah, Ciro Coletta, Bartosz Szczesny and Csaba Szabo
Molecular Pharmacology October 2014, 86 (4) 450-462; DOI: https://doi.org/10.1124/mol.114.094318
Attila Brunyanszki
Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas
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Gabor Olah
Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas
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Ciro Coletta
Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas
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Bartosz Szczesny
Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas
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Csaba Szabo
Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas
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Abstract

We investigated the regulation of mitochondrial poly(ADP-ribose) polymerase 1 (PARP1) by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) system during oxidative stress in U937 monocytes. Oxidative stress induced an early (10 minutes) mitochondrial DNA damage, and concomitant activation of PARP1 in the mitochondria. These early events were followed by a progressive mitochondrial oxidant production and nuclear PARP1 activation (by 6 hours). These processes led to a functional impairment of mitochondria, culminating in cell death of mixed (necrotic/apoptotic) type. β-Adrenoceptor blockade with propranolol or inhibition of its downstream cAMP/PKA signaling attenuated, while β-adrenoceptor agonists and cAMP/PKA activators enhanced, the oxidant-mediated PARP1 activation. In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain). Inhibition of the β-adrenergic receptor/cAMP/PKA axis protected against the oxidant-mediated cell injury. Propranolol also suppressed PARP1 activation in peripheral blood leukocytes during bacterial lipopolysaccharide (LPS)-induced systemic inflammation in mice. We conclude that the activation of mitochondrial PARP1 is an early, active participant in oxidant-induced cell death, which is under the control of β-adrenoceptor/cAMP/PKA axis through the regulation of PARP1 activity by PARP1 phosphorylation.

Footnotes

    • Received June 18, 2014.
    • Accepted July 28, 2014.
  • This work was supported by the National Institutes of Health [Grant GM060338] (to C.S.); the Shriners Hospitals for Children [Grant 85800] (to C.S.); and the American Heart Association [Grant 12POST12060643] (to C.C.).

  • dx.doi.org/10.1124/mol.114.094318.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (4)
Molecular Pharmacology
Vol. 86, Issue 4
1 Oct 2014
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Research ArticleArticle

Mitochondrial PARP1 Is Regulated by β-Receptors

Attila Brunyanszki, Gabor Olah, Ciro Coletta, Bartosz Szczesny and Csaba Szabo
Molecular Pharmacology October 1, 2014, 86 (4) 450-462; DOI: https://doi.org/10.1124/mol.114.094318

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Research ArticleArticle

Mitochondrial PARP1 Is Regulated by β-Receptors

Attila Brunyanszki, Gabor Olah, Ciro Coletta, Bartosz Szczesny and Csaba Szabo
Molecular Pharmacology October 1, 2014, 86 (4) 450-462; DOI: https://doi.org/10.1124/mol.114.094318
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