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Deficient Ryanodine Receptor S-Nitrosylation Increases Sarcoplasmic Reticulum Calcium Leak and Arrhythmogenesis in Cardiomyocytes

Daniel R. Gonzalez, Farideh Beigi, Adriana V. Treuer and Joshua M. Hare
Proceedings of the National Academy of Sciences of the United States of America
Vol. 104, No. 51 (Dec. 18, 2007), pp. 20612-20617
Stable URL: http://www.jstor.org/stable/25450940
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Deficient Ryanodine Receptor S-Nitrosylation Increases Sarcoplasmic Reticulum Calcium Leak and Arrhythmogenesis in Cardiomyocytes
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Abstract

Altered Ca²⁺ homeostasis is a salient feature of heart disease, where the calcium release channel ryanodine receptor (RyR) plays a major role. Accumulating data support the notion that neuronal nitric oxide synthase (NOS1) regulates the cardiac RyR via S-nitrosylation. We tested the hypothesis that NOS1 deficiency impairs RyR S-nitrosylation, leading to altered Ca²⁺ homeostasis. Diastolic Ca²⁺ levels are elevated in ${\rm NOS}1^{-/-}$ and ${\rm NOS}1/{\rm NOS}3^{-/-}$ but not ${\rm NOS}3^{-/-}$ myocytes compared with wild-type (WT), suggesting diastolic Ca²⁺ leakage. Measured leak was increased in ${\rm NOS}1^{-/-}$ and ${\rm NOS}1/{\rm NOS}3^{-/-}$ but not in ${\rm NOS}3^{-/-}$ myocytes compared with WT. Importantly, ${\rm NOS}1^{-/-}$ and ${\rm NOS}1/{\rm NOS}3^{-/-}$ myocytes also exhibited spontaneous calcium waves. Whereas the stoichiometry and binding of FK-binding protein 12.6 to RyR and the degree of RyR phosphorylation were not altered in ${\rm NOS}1^{-/-}$ hearts, RyR2 S-nitrosylation was substantially decreased, and the level of thiol oxidation increased. Together, these findings demonstrate that NOS1 deficiency causes RyR2 hyponitrosylation, leading to diastolic Ca²⁺ leak and a proarrhythmic phenotype. NOS1 dysregulation may be a proximate cause of key phenotypes associated with heart disease.

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