(A) Calcium transients begin with the initial influx of Ca²⁺ via L-type Ca²⁺ channels followed by Ca²⁺ release from the SR via RyR2s, which culminates in contraction. During relaxation, Ca²⁺ reuptake occurs via the PLN-regulated Ca²⁺ pump SERCA2a. The major Ca²⁺ buffering protein in the SR is CASQ2. High [Ca²⁺]_SR converts monomeric CASQ2 (bound to the RyR2-triadin-junctin complex) to the polymeric CASQ2 form that buffers Ca²⁺ and remains close to the complex in the jSR. Calstabin2 and monomeric CASQ2 bind to the complex and stabilize RyR2 activity. (B) Altered Ca²⁺ handling in CASQ2-deficient myocytes. As Song et al. report (10), in CASQ2-deficient mouse myocytes, RyR2 expression is significantly upregulated and calreticulin abundance is slightly increased. There is a decrease in Ca²⁺ in the SR. Despite altered Ca²⁺ handling in these animals under resting conditions, these compensatory changes in protein expression appear to help maintain relatively normal heart function. However, under catecholamine- or exercise-induced stress, RyR2 instability increases, leading to an increased risk of cardiac arrhythmia. nSR, nonjunctional SR.