Store-dependent deactivation: Cooling the chain-reaction of myocardial calcium signaling

► CICR is counterbalanced by store-dependent deactivation due to reciprocal decrease in [Ca2 +]SR. ► RyR2 regulation by luminal Ca2 + is mediated by CASQ2 inhibiting RyR2 at low luminal Ca2 +. ► Luminal Ca2 + allosterically modulates RyR2 sensitivity to cytosolic Ca2 +. ► Genetic and acquired defects in RyR2 complex dysregulate store-dependent deactivation. ► Impairment of store-dependent deactivation results in cardiac arrhythmias.