Intact beta-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
| Autor: | Héctor H. Valdivia, Timothy A. Hacker, Craig Weber, Emily F. Farrell, Manorama C. John, Joseph A. Scherman, Patricia A. Powers, Nancy A. Benkusky |
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| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_specialty
Physiology Hyperphosphorylation Stimulation Biology Ryanodine receptor 2 Mice Internal medicine Receptors Adrenergic beta medicine Animals Phosphorylation Protein kinase A Receptor Heart Failure Mice Knockout Ryanodine receptor Ryanodine Receptor Calcium Release Channel musculoskeletal system medicine.disease Cyclic AMP-Dependent Protein Kinases Endocrinology Heart failure cardiovascular system Cardiology and Cardiovascular Medicine tissues |
| Zdroj: | Circulation research. 101(8) |
| ISSN: | 1524-4571 |
| Popis: | 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 Ca 2+ release by augmenting the sensitivity of the RyR2 channel to diastolic Ca 2+ . 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 β-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 β-adrenergic stimulation and PKA phosphorylation of Ser2808 in heart failure progression and cellular Ca 2+ handling. We found that the RyR2-S2808A mutation does not alter the β-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 [Ca 2+ ]. 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. |
| Databáze: | OpenAIRE |
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