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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes

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Ryanodine receptor/calcium release channel PKA phosphorylation: a critical mediator of heart failure progression

Xander H T Wehrens1, Stephan E Lehnart, Steven Reiken

  • 1Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

Proceedings of the National Academy of Sciences of the United States of America
|January 13, 2006
PubMed

Insights

Defective regulation of the cardiac ryanodine receptor (RyR2) causes heart failure and arrhythmias. PKA phosphorylation at Ser-2808 leads to leaky RyR2 channels, worsening cardiac dysfunction.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Physiology

Background:

  • Defective regulation of the cardiac ryanodine receptor (RyR2) is implicated in heart failure and arrhythmias.
  • Diastolic calcium leak through RyR2 channels contributes to impaired contractility and sudden cardiac death.
  • Chronic stress response leads to PKA hyperphosphorylation of RyR2 at Ser-2808 in heart failure patients.

Purpose of the Study:

  • To investigate the role of Ser-2808 as the functional PKA phosphorylation site on RyR2.
  • To determine if preventing PKA phosphorylation at Ser-2808 protects against cardiac dysfunction.

Main Methods:

  • Development of RyR2-S2808A mice to create a non-phosphorylatable RyR2 channel.
  • Assessment of cardiac function and protection against heart failure after myocardial infarction in these mice.

Main Results:

  • RyR2-S2808A mice, unable to undergo PKA phosphorylation at Ser-2808, were protected against heart failure development post-myocardial infarction.
  • PKA phosphorylation of RyR2 Ser-2808 reduces calstabin2 binding, leading to leaky RyR2 channels.

Conclusions:

  • PKA phosphorylation of Ser-2808 on the RyR2 channel is a critical mediator of progressive cardiac dysfunction.
  • Targeting RyR2 Ser-2808 phosphorylation may offer a therapeutic strategy for heart failure and arrhythmias.

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