@article{8506991,
  abstract     = {{Rationale: The regulation of calcium (Ca2+) homeostasis by -adrenergic receptor (AR) activation provides the essential underpinnings of sympathetic regulation of myocardial function, as well as a basis for understanding molecular events that result in hypertrophic signaling and heart failure. Sympathetic stimulation of the AR not only induces protein phosphorylation but also activates nitric oxide-dependent signaling, which modulates cardiac contractility. Nonetheless, the role of nitric oxide in AR-dependent regulation of Ca2+ handling has not yet been explicated fully. Objective: To elucidate the role of protein S-nitrosylation, a major transducer of nitric oxide bioactivity, on AR-dependent alterations in cardiomyocyte Ca2+ handling and hypertrophy. Methods and Results: Using transgenic mice to titrate the levels of protein S-nitrosylation, we uncovered major roles for protein S-nitrosylation, in general, and for phospholamban and cardiac troponin C S-nitrosylation, in particular, in AR-dependent regulation of Ca2+ homeostasis. Notably, S-nitrosylation of phospholamban consequent upon AR stimulation is necessary for the inhibitory pentamerization of phospholamban, which activates sarcoplasmic reticulum Ca2+-ATPase and increases cytosolic Ca2+ transients. Coincident S-nitrosylation of cardiac troponin C decreases myocardial sensitivity to Ca2+. During chronic adrenergic stimulation, global reductions in cellular S-nitrosylation mitigate hypertrophic signaling resulting from Ca2+ overload. Conclusions: S-Nitrosylation operates in concert with phosphorylation to regulate many cardiac Ca2+-handling proteins, including phospholamban and cardiac troponin C, thereby playing an essential and previously unrecognized role in cardiac Ca2+ homeostasis. Manipulation of the S-nitrosylation level may prove therapeutic in heart failure.}},
  author       = {{Irie, Tomoya and Sips, Patrick and Kai, Shinichi and Kida, Kotaro and Ikeda, Kohei and Hirai, Shuichi and Moazzami, Kasra and Jiramongkolchai, Pawina and Bloch, Donald B and Doulias, Paschalis-Thomas and Armoundas, Antonis A and Kaneki, Masao and Ischiropoulos, Harry and Kranias, Evangelia and Bloch, Kenneth D and Stamler, Jonathan S and Ichinose, Fumito}},
  issn         = {{0009-7330}},
  journal      = {{CIRCULATION RESEARCH}},
  keywords     = {{BRIDGE CYCLING KINETICS,TROPONIN-C MUTATIONS,S-NITROSYLATION,MYOCARDIAL-CONTRACTILITY,MOUSE HEARTS,PHOSPHOLAMBAN,PHOSPHORYLATION,TEMPERATURE,MYOCYTES,DENITROSYLATION,beta adrenergic,calcium,heart failure,myocardial contraction,nitric,oxide,receptors}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{793--803}},
  title        = {{Nitrosylation of calcium-handling proteins in cardiac adrenergic signaling and hypertrophy}},
  url          = {{http://doi.org/10.1161/CIRCRESAHA.115.307157}},
  volume       = {{117}},
  year         = {{2015}},
}

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