Phosphorylation of RyR2 Ser-2814 by CaMKII mediates β1-adrenergic stress induced Ca -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) Ca leak. However, the exact mechanisms for this remained unspecified so far. This study shows that Ca /calmodulin-dependent protein kinase II (CaMKII)-specific phosphorylation of ryanodine receptor type 2 at Ser-2814 is the pivotal mechanism by which SR Ca 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 Ca leak and consequently displayed improved postrest potentiation of systolic Ca release under adrenergic stress compared to littermate wild-type cells.