Ryanodine receptor/calcium release channel PKA phosphorylation: a critical mediator of heart failure progression.
Defective regulation of the cardiac ryanodine receptor (RyR2)/calcium release channel, required for excitation-contraction coupling in the heart, has been linked to cardiac arrhythmias and heart failure. For example, diastolic calcium "leak" via RyR2 channels in the sarcoplasmic reticulum has been identified as an important factor contributing to impaired contractility in heart failure and ventricular arrhythmias that cause sudden cardiac death. In patients with heart failure, chronic activation of the "fight or flight" stress response leads to protein kinase A (PKA) hyperphosphorylation of RyR2 at Ser-2808. PKA phosphorylation of RyR2 Ser-2808 reduces the binding affinity of the channel-stabilizing subunit calstabin2, resulting in leaky RyR2 channels. We developed RyR2-S2808A mice to determine whether Ser-2808 is the functional PKA phosphorylation site on RyR2. Furthermore, mice in which the RyR2 channel cannot be PKA phosphorylated were relatively protected against the development of heart failure after myocardial infarction. Taken together, these data show that PKA phosphorylation of Ser-2808 on the RyR2 channel appears to be a critical mediator of progressive cardiac dysfunction after myocardial infarction.
Wehrens
Xander H T
XH
Department 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.
Lehnart
Stephan E
SE
Reiken
Steven
S
Vest
John A
JA
Wronska
Anetta
A
Marks
Andrew R
AR
D000818:Animals; D002303:Cardiac Output, Low / Q000201:enzymology* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D018450:Disease Progression; D006333:Heart Failure / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases