It is accepted that CPVT arrhythmias result from repetitive, premature activation of RyR2. It has long been known that RyR is activated by elevation of luminal Ca2+ beyond a certain threshold (Palade et al. 1983; Venetucciet al. 2008). Here, we refer to this phenomenon as store overload-induced Ca2+ release (SOICR). RyR2 CPVT mutant channels expressed in the human embryonic kidney cell line HEK-293 were activated by much lower luminal Ca2+ levels than wild-type (wt)(Jiang et al. 2004, 2005). Critically, the frequency of Ca2+ oscillations was markedly increased and the size of the Ca2+ store was decreased. When single channel activities of RyR2 CPVT mutants were measured in planar lipid bilayers with 45 nM cytoplasmic Ca2+, incremental elevation of luminal Ca2+ from 0 to 1000 μM increased the probability of opening to 0.3–0.4 for CPVT mutant RyR2 vs. 0.02 for wt RyR2. These results demonstrate that RyR2 CPVT mutant channels, in isolation from other sarcoplasmic reticulum (SR) proteins, manifest a lower SOICR threshold than wt RyR2.