Published online before print August 23, 2007, doi: 10.1161/CIRCRESAHA.107.153007
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Submitted on March 28, 2007
Revised on July 23, 2007
Accepted on August 14, 2007
Intact 
-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 ;
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.
* To whom correspondence should be addressed. 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 
-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 -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 -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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