Abstract |
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 beta- 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 beta- 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 beta- 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.
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Authors | Nancy A Benkusky, Craig S Weber, Joseph A Scherman, Emily F Farrell, Timothy A Hacker, Manorama C John, Patricia A Powers, Héctor H Valdivia |
Journal | Circulation research
(Circ Res)
Vol. 101
Issue 8
Pg. 819-29
(Oct 12 2007)
ISSN: 1524-4571 [Electronic] United States |
PMID | 17717301
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Receptors, Adrenergic, beta
- Ryanodine Receptor Calcium Release Channel
- Cyclic AMP-Dependent Protein Kinases
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Topics |
- Animals
- Cyclic AMP-Dependent Protein Kinases
(genetics, metabolism)
- Heart Failure
(genetics, metabolism)
- Mice
- Mice, Knockout
- Phosphorylation
- Receptors, Adrenergic, beta
(genetics, metabolism, physiology)
- Ryanodine Receptor Calcium Release Channel
(deficiency, genetics, metabolism)
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