RyR2 phosphorylation at serine-2814 increases cardiac tolerance to arrhythmogenic Ca2+ alternans in mice

Abstract

Alternation in the amplitude of Ca2+ transients (Ca2+ alternans) is a known substrate for life-threatening arrhythmias that emerge at high beating rates. β-adrenergic stimulation promotes cardiac adaptation to beat at high frequencies without alternans. Ryanodine receptors (RyR2) affect the propensity for developing Ca2+ alternans but their fine tuning involved in adaptation to tachycardia is not fully elucidated. We aim to determine the impact of RyR2 phosphorylation at Serine 2814 on Ca2+ alternans occurrence. Cytosolic Ca2+ concentration was monitored in intact hearts and ventricular cardiomyocytes. The response obtained from knock-in mice harboring S2814A (non-phosphorylatable) and S2814D (pseudo-phosphorylated) demonstrate that phosphorylation of S2814-RyR2 increases cardiac tolerance to fast Ca2+ cycling. Indeed, β-adrenergic stimulation only reduced Ca2+ alternans in WT, supporting that phosphorylation of S2814-RyR2 is necessary for cardiac adaptation against Ca2+ alternans.