Overexpression of CaMKIIδc in RyR2R4496C+/- knock-in mice leads to altered intracellular Ca2+ handling and increased mortality.

Objectives We investigated whether increased Ca 2+ /calmodulin-dependent kinase II (CaMKII) activity aggravates defective excitation-contraction coupling and proarrhythmic activity in mice expressing R4496C mutated cardiac ryanodine receptors (RyR2). Background RyR2 dysfunction is associated with arrhythmic events in inherited and acquired cardiac disease. Methods CaMKIIδc transgenic mice were crossbred with RyR2 R4496C+/− knock-in mice. Results Heart weight-to-body weight ratio in CaMKIIδc/RyR2 R4496C and CaMKIIδc mice was similarly increased approximately 3-fold versus wild-type mice (p R4496C and CaMKIIδc mice. Sarcoplasmic reticulum Ca 2+ content in isolated myocytes was decreased to a similar extent in CaMKIIδc/RyR2 R4496C and CaMKIIδc mice. However, relaxation parameters and Ca 2+ decay at 1 Hz were prolonged significantly in CaMKIIδc mice versus CaMKIIδc/RyR2 R4496C mice. Sarcoplasmic reticulum Ca 2+ spark frequency and characteristics indicated increased sarcoplasmic reticulum Ca 2+ leak in CaMKIIδc/RyR2 R4496C versus CaMKIIδc myocytes (p R4496C versus CaMKIIδc mice. Increased arrhythmias in vivo (67% vs. 25%; p R4496C mice, which died prematurely with only 30% alive (vs. 60% for CaMKIIδc, p Conclusions CaMKIIδc overexpression in RyR2 R4496C+/− knock-in mice increases the propensity toward triggered arrhythmias, which may impair survival. CaMKII contributes to further destabilization of a mutated RyR2 receptor.