Role of the Ryanodine Receptor/Calcium Release Channel in Beta-adrenergic Receptor Blocker Treatment of Heart Failure

Abstract

To explore the role of protein kinase A (PKA) phosphorylation of the cardiac ryanodine receptor (RyR2)/calcium release channel in the treatment of heart failure (HF) using beta-adrenergic receptor blockers (beta-blockers) we generated a knock-in mouse with aspartic acid replacing serine at residue 2808 in RyR2 (RyR2-S2808D). This mutation mimics constitutive PKA hyperphosphorylation of RyR2, a condition that occurs during HF. RyR2-S2808D+/+ mice developed an age-dependent cardiomyopathy characterized by moderate cardiac dysfunction and mild left ventricular dilatation indicating that PKA hyperphosphorylation of RyR2 alone can cause cardiac dysfunction. Following myocardial infarction (MI), RyR2-S2808D+/+ mice exhibited increased mortality compared to WT littermates. Treatment with the rycal S107, a 1,4-benzothiazepine derivative that inhibits PKA hyperphosphorylation-induced depletion of calstabin2 from the RyR2 complex, for 4 weeks significantly reduced HF progression in WT and RyR2-S2808D+/+ mice, confirming the important role of calstabin2 binding to RyR2 in preventing HF progression. In contrast, following MI, treatment with the beta-adrenergic receptor blocker (beta-blocker) metoprolol improved cardiac function in WT but not in RyR2-S2808D+/+ mice, indicating the important role of inhibition of PKA hyperphosphorylation of RyR2 as a key mechanism underlying the beneficial effects of beta-blockers in HF. Taken together, these data show that chronic RyR2 PKA hyperphosphorylation alone can cause a cardiomyopathy, preventing calstabin2 depletion from the RyR2 macromolecular complex can inhibit HF progression, and PKA phosphorylation of RyR2 is an important determinant of the therpaeutic efficacy of beta-blocker therapy of HF.