Figure 6. A model for CPVT based on abnormal SR Ca²⁺ homeostasis in CASQ2-deficient myocytes.

(A) Under resting conditions, SR Ca²⁺ (blue circles) is plentiful and buffered by CASQ2 (blue rectangles) in WT myocyte. Ca²⁺ influx via L-type Ca²⁺ channel (left side) causes Ca²⁺-induced Ca²⁺ release (CICR) through cardiac RyR2 channels (purple). Reuptake of cytosolic Ca²⁺ (black arrows) occurs via the SERCA/PLN complex (orange). When SR Ca²⁺ concentration falls (right half), CASQ2 binds to the RyR2 channel, closing the channel (x), thus preventing Ca²⁺ leak (right side arrow). (B) In CASQ2-deficient myocytes, CRT (brown symbols) replaces CASQ2. Total SR Ca²⁺ is lower than in WT myocytes due to lower Ca²⁺-binding capacity by CRT (50% of CASQ2) and diastolic Ca²⁺ leak (red dashed arrows) through abundant RyR2 channels and inadequate calstabin. SERCA2-mediated Ca²⁺ reuptake may also be impaired (dashed black arrows) due to increased free Ca²⁺ gradient given lower Ca²⁺-binding capacity of CRT. Total SR Ca²⁺ transients and cytosolic Ca²⁺ are near normal. (C) Catecholaminergic stress applied to CASQ2-deficient myocytes phosphorylates RyR2 channels and PLN, dissociating calstabin from RyR2. Excessive RyR2 activity causes extensive diastolic Ca²⁺ leak, further depletes SR Ca²⁺, reduces SR Ca²⁺ transients, and increases cytosolic Ca²⁺ levels. Excess cytosolic Ca²⁺, effluxed via the Na⁺/Ca²⁺ exchanger, increases Na⁺ entry into myocyte, which increases the probability of delayed after-polarization and cardiac arrhythmia. Toxicity of Ca²⁺ overload may increase myocyte death.