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(Circulation Research. 2007;101:819.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Intact ß-Adrenergic Response and Unmodified Progression Toward Heart Failure in Mice With Genetic Ablation of a Major Protein Kinase A Phosphorylation Site in the Cardiac Ryanodine Receptor

Nancy A. Benkusky, Craig S. Weber, Joseph A. Scherman, Emily F. Farrell, Timothy A. Hacker, Manorama C. John, Patricia A. Powers, Héctor H. Valdivia

From the Departments of Physiology (N.A.B., C.S.W., J.A.S., E.F.F., H.H.V.) and Medicine (T.A.H.) and the Biotechnology Center (M.C.J., P.A.P.), University of Wisconsin, Madison.

Correspondence to Héctor H. Valdivia, MD, PhD, 601 Science Dr, Madison, WI 53711. E-mail valdivia{at}physiology.wisc.edu

Increased phosphorylation of the cardiac ryanodine receptor (RyR)2 by protein kinase A (PKA) at the phosphoepitope encompassing Ser2808 has been advanced as a central mechanism in the pathogenesis of cardiac arrhythmias and heart failure. In this scheme, persistent activation of the sympathetic system during chronic stress leads to PKA "hyperphosphorylation" of RyR2-S2808, which increases Ca²⁺ release by augmenting the sensitivity of the RyR2 channel to diastolic Ca²⁺. This gain-of-function is postulated to occur with the unique participation of RyR2-S2808, and other potential PKA phosphorylation sites have been discarded. Although it is clear that RyR2 is among the first proteins in the heart to be phosphorylated by ß-adrenergic stimulation, the functional impact of phosphorylation in excitation–contraction coupling and cardiac performance remains unclear. We used gene targeting to produce a mouse model with complete ablation of the RyR2-S2808 phosphorylation site (RyR2-S2808A). Whole-heart and isolated cardiomyocyte experiments were performed to test the role of ß-adrenergic stimulation and PKA phosphorylation of Ser2808 in heart failure progression and cellular Ca²⁺ handling. We found that the RyR2-S2808A mutation does not alter the ß-adrenergic response, leaves cellular function almost unchanged, and offers no significant protection in the maladaptive cardiac remodeling induced by chronic stress. Moreover, the RyR2-S2808A mutation appears to modify single-channel activity, although modestly and only at activating [Ca²⁺]. Taken together, these results reveal some of the most important effects of PKA phosphorylation of RyR2 but do not support a major role for RyR2-S2808 phosphorylation in the pathogenesis of cardiac dysfunction and failure.

Key Words: excitation–contraction coupling • sarcoplasmic reticulum • Ca²⁺ sparks • lipid bilayers

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Regulation of Ryanodine Receptors in the Heart

Stephan Lehnart and Andrew R. Marks
Circ. Res. 2007 101: 746-749. [Extract] [Full Text] [PDF]

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