Transgenic titration of protein S-nitrosylation in mice demonstrated that S-nitrosylation of phospholamban and cardiac troponin C is essential for β-adrenergic regulation of calcium homeostasis.
S-Nitrosylation operates in concert with phosphorylation to regulate cardiac Ca2+-handling proteins, revealing a previously unrecognized role in cardiac Ca2+ homeostasis and a potential therapeutic target for heart failure.
Rationale: The regulation of calcium (Ca 2+ ) homeostasis by β-adrenergic receptor (βAR) 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 βAR not only induces protein phosphorylation but also activates nitric oxide–dependent signaling, which modulates cardiac contractility. Nonetheless, the role of nitric oxide in βAR-dependent regulation of Ca 2+ handling has not yet been explicated fully. Objective: To elucidate the role of protein S-nitrosylation, a major transducer of nitric oxide bioactivity, on βAR-dependent alterations in cardiomyocyte Ca 2+ 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 βAR-dependent regulation of Ca 2+ homeostasis. Notably, S-nitrosylation of phospholamban consequent upon βAR stimulation is necessary for the inhibitory pentamerization of phospholamban, which activates sarcoplasmic reticulum Ca 2+ -ATPase and increases cytosolic Ca 2+ transients. Coincident S-nitrosylation of cardiac troponin C decreases myocardial sensitivity to Ca 2+ . During chronic adrenergic stimulation, global reductions in cellular S-nitrosylation mitigate hypertrophic signaling resulting from Ca 2+ overload. Conclusions: S-Nitrosylation operates in concert with phosphorylation to regulate many cardiac Ca 2+ -handling proteins, including phospholamban and cardiac troponin C, thereby playing an essential and previously unrecognized role in cardiac Ca 2+ homeostasis. Manipulation of the S-nitrosylation level may prove therapeutic in heart failure.
Irie et al. (Mon,) conducted a other in Cardiac adrenergic signaling and hypertrophy. Transgenic titration of protein S-nitrosylation was evaluated on Cardiomyocyte Ca2+ handling and hypertrophy. Transgenic titration of protein S-nitrosylation in mice demonstrated that S-nitrosylation of phospholamban and cardiac troponin C is essential for β-adrenergic regulation of calcium homeostasis.