title: Novel Roles for Peroxynitrite in Angiotensin II and CaMKII Signaling.
abstract: Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) oxidation controls excitability and viability. While hydrogen peroxide (H2O2) affects Ca(2+)-activated CaMKII in vitro, Angiotensin II (Ang II)-induced CaMKIIδ signaling in cardiomyocytes is Ca(2+) independent and requires NADPH oxidase-derived superoxide, but not its dismutation product H2O2. To better define the biological regulation of CaMKII activation and signaling by Ang II, we evaluated the potential for peroxynitrite (ONOO(-)) to mediate CaMKII activation and downstream Kv4.3 channel mRNA destabilization by Ang II. In vitro experiments show that ONOO(-) oxidizes and modestly activates pure CaMKII in the absence of Ca(2+)/CaM. Remarkably, this apokinase stimulation persists after mutating known oxidation targets (M281, M282, C290), suggesting a novel mechanism for increasing baseline Ca(2+)-independent CaMKII activity. The role of ONOO(-) in cardiac and neuronal responses to Ang II was then tested by scavenging ONOO(-) and preventing its formation by inhibiting nitric oxide synthase. Both treatments blocked Ang II effects on Kv4.3, tyrosine nitration and CaMKIIδ oxidation and activation. Together, these data show that ONOO(-) participates in Ang II-CaMKII signaling. The requirement for ONOO(-) in transducing Ang II signaling identifies ONOO(-), which has been viewed as a reactive damaging byproduct of superoxide and nitric oxide, as a mediator of GPCR-CaMKII signaling.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261 USA.
authors.forename: Chaoming
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Biology and Stark Neuroscience Research Institute, Indiana University School of Medicine, 320 West 15th Street, Indianapolis, IN 46202 USA.
authors.forename: Swarna S
authors.initials: SS
authors.lastname: Ramaswamy
authors.affiliation: Department of Biochemistry and Molecular Biology and Stark Neuroscience Research Institute, Indiana University School of Medicine, 320 West 15th Street, Indianapolis, IN 46202 USA.
authors.forename: Derrick E
authors.initials: DE
authors.lastname: Johnson
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261 USA.
authors.forename: Dario A
authors.initials: DA
authors.lastname: Vitturi
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261 USA.
authors.forename: Franciso J
authors.initials: FJ
authors.lastname: Schopfer
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261 USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
authors.affiliation: Department of Biochemistry and Molecular Biology and Stark Neuroscience Research Institute, Indiana University School of Medicine, 320 West 15th Street, Indianapolis, IN 46202 USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Hudmon
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261 USA.
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Levitan
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002460:Cell Line; D008715:Methionine / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D000804:Angiotensin II; D030421:Peroxynitrous Acid; D014443:Tyrosine; D008715:Methionine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2