Details

Autor(en) / Beteiligte

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

Titel

Intact β-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

Ist Teil von

• Circulation research, 2007-10, Vol.101 (8), p.819-829

Ort / Verlag

Hagerstown, MD: American Heart Association, Inc

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 release by augmenting the sensitivity of the RyR2 channel to diastolic Ca. 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 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]. 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.