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(Circulation Research. 2008;102:e65.)
© 2008 American Heart Association, Inc.

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Adrenergic Regulation of Cardiac Contractility Does Not Involve Phosphorylation of the Cardiac Ryanodine Receptor at Serine 2808

Scott M. MacDonnell^*, Gerardo García-Rivas^*, Joseph A. Scherman^*, Hajime Kubo, Xiongwen Chen, Héctor Valdivia, Steven R. Houser

From the Department of Physiology (S.M., H.K., X.C., S.R.H.), Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa; and Department of Physiology (G.G.-R., J.A.S., H.V.), University of Wisconsin Medical School, Madison.

Correspondence to Dr Steven R. Houser, 3400 N Broad St, Philadelphia, PA 19140. E-mail srhouser{at}temple.edu

The sympathetic nervous system is a critical regulator of cardiac function (heart rate and contractility) in health and disease. Sympathetic nervous system agonists bind to adrenergic receptors that are known to activate protein kinase A, which phosphorylates target proteins and enhances cardiac performance. Recently, it has been proposed that protein kinase A–mediated phosphorylation of the cardiac ryanodine receptor (the Ca²⁺ release channel of the sarcoplasmic reticulum at a single residue, Ser2808) is a critical component of sympathetic nervous system regulation of cardiac function. This is a highly controversial hypothesis that has not been confirmed by several independent laboratories. The present study used a genetically modified mouse in which Ser2808 was replaced by alanine (S2808A) to prevent phosphorylation at this site. The effects of isoproterenol (a sympathetic agonist) on ventricular performance were compared in wild-type and S2808A hearts, both in vivo and in isolated hearts. Isoproterenol effects on L-type Ca²⁺ current (I_CaL), sarcoplasmic reticulum Ca²⁺ release, and excitation–contraction coupling gain were also measured. Our results showed that isoproterenol caused significant increases in cardiac function, both in vivo and in isolated hearts, and there were no differences in these contractile effects in wild-type and S2808A hearts. Isoproterenol increased I_CaL, the amplitude of the Ca²⁺ transient and excitation–contraction coupling gain, but, again, there were no significant differences between wild-type and S2808A myocytes. These results show that protein kinase A phosphorylation of ryanodine receptor Ser2808 does not have a major role in sympathetic nervous system regulation of normal cardiac function.

Key Words: ryanodine receptor • PKA phosphorylation • excitation–contraction coupling • β-adrenergic regulation

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What Are the Consequences of Phosphorylation and Hyperphosphorylation of Ryanodine Receptors in Normal and Failing Heart?

John H.B. Bridge and Eleonora Savio-Galimberti
Circ. Res. 2008 102: 995-997. [Extract] [Full Text] [PDF]

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