Protein kinase A phosphorylation of the cardiac calcium release channel (ryanodine receptor) in normal and failing hearts. Role of phosphatases and response to isoproterenol.

Abstract

The cardiac ryanodine receptor/calcium release channel (RyR2) on the sarcoplasmic reticulum (SR) comprises a macromolecular complex that includes a kinase and two phosphatases that are bound to the channel via targeting proteins. We previously found that the RyR2 is protein kinase A (PKA)-hyperphosphorylated in end-stage human heart failure. Because heart failure is a progressive disease that often evolves from hypertrophy, we analyzed the RyR2 macromolecular complex in several animal models of cardiomyopathy that lead to heart failure, including hypertrophy, and at different stages of disease progression. We now show that RyR2 is PKA-hyperphosphorylated in diverse models of heart failure and that the degree of RyR2 PKA phosphorylation correlates with the degree of cardiac dysfunction. Interestingly, we show that RyR2 PKA hyperphosphorylation can be lost during perfusion of isolated hearts due to the activity of the endogenous phosphatases in the RyR2 macromolecular complex. Moreover, infusion of isoproterenol resulted in PKA phosphorylation of RyR2 in rat, indicating that systemic catecholamines can activate phosphorylation of RyR2 in vivo. These studies extend our previous analyses of the RyR2 macromolecular complex, show that both the kinase and phosphatase activities in the macromolecular complex are regulated physiologically in vivo, and suggest that RyR2 PKA hyperphosphorylation is likely a general feature of heart failure.

• Authors: Steven Reiken, Marta Gaburjakova, Silvia Guatimosim, Ana M Gomez, Jeanine D'Armiento, Daniel Burkhoff, Jie Wang, Guy Vassort, W Jonathan Lederer, Andrew R Marks
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 1 Pg. 444-53 (Jan 03 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12401811 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Calcium-Binding Proteins
• Macromolecular Substances
• Receptors, Adrenergic, beta
• Ryanodine Receptor Calcium Release Channel
• Sympathomimetics
• phospholamban
• Cyclic AMP-Dependent Protein Kinases
• Matrix Metalloproteinase 1
• Isoproterenol
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium-Binding Proteins (metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Disease Models, Animal
• Heart (physiology, physiopathology)
• Heart Failure (metabolism, physiopathology)
• Humans
• Isoproterenol (pharmacology)
• Macromolecular Substances
• Male
• Matrix Metalloproteinase 1 (genetics, metabolism)
• Mice
• Myocardial Infarction (metabolism)
• Myocardium (metabolism)
• Myocytes, Cardiac (drug effects, metabolism)
• Patch-Clamp Techniques
• Phosphorylation
• Rats
• Rats, Inbred Dahl
• Rats, Wistar
• Receptors, Adrenergic, beta (genetics, metabolism)
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Sympathomimetics (pharmacology)