Phosphorylation of RyR2 Ser‐2814 by CaMKII mediates β1‐adrenergic stress induced Ca2+‐leak from the sarcoplasmic reticulum

Adrenergic stimulation, while being the central mechanism of cardiac positive inotropy, is a universally acknowledged inductor of undesirable sarcoplasmic reticulum (SR) Ca2+ leak. However, the exact mechanisms for this remained unspecified so far. This study shows that Ca2+/calmodulin‐dependent protein kinase II (CaMKII)‐specific phosphorylation of ryanodine receptor type 2 at Ser‐2814 is the pivotal mechanism by which SR Ca2+ leak develops downstream of β1‐adrenergic stress by increase of the leak/load relationship. Cardiomyocytes with a Ser‐2814 phosphoresistant mutation (S2814A) were protected from isoproterenol‐induced SR Ca2+ leak and consequently displayed improved postrest potentiation of systolic Ca2+ release under adrenergic stress compared to littermate wild‐type cells