S-Nitrosylation of Calcium-Handling Proteins in Cardiac Adrenergic Signaling and Hypertrophy

Circ Res. 2015 Oct 9;117(9):793-803. doi: 10.1161/CIRCRESAHA.115.307157. Epub 2015 Aug 10.


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.

Keywords: beta adrenergic; calcium; heart failure; myocardial contraction; nitric oxide; receptors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Aldehyde Oxidoreductases
  • Animals
  • Calcium / metabolism*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cells, Cultured
  • Hypertrophy
  • Immunoblotting
  • Isoproterenol / pharmacology
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Nitric Oxide / metabolism*
  • Phosphorylation
  • Receptors, Adrenergic, beta / metabolism*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Signal Transduction / drug effects
  • Troponin I / genetics
  • Troponin I / metabolism


  • Adrenergic beta-Agonists
  • Calcium-Binding Proteins
  • Receptors, Adrenergic, beta
  • Troponin I
  • phospholamban
  • Nitric Oxide
  • Aldehyde Oxidoreductases
  • formaldehyde dehydrogenase, glutathione-independent
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Isoproterenol
  • Calcium