CPVT (catecholaminergic polymorphic ventricular tachycardia) is an inherited 
life-threatening arrhythmogenic disorder. CPVT is caused by DADs (delayed 
after-depolarizations) that are induced by spontaneous Ca2+ release during SR 
(sarcoplasmic reticulum) Ca2+ overload, a process also known as SOICR 
(store-overload-induced Ca2+ release). A number of mutations in the cardiac 
ryanodine receptor RyR2 are linked to CPVT. Many of these CPVT-associated RyR2 
mutations enhance the propensity for SOICR and DADs by sensitizing RyR2 to 
luminal or luminal/cytosolic Ca2+ activation. Recently, a novel CPVT RyR2 
mutation, G230C, was found to increase the cytosolic, but not the luminal, Ca2+ 
sensitivity of single RyR2 channels in lipid bilayers. This observation led to 
the suggestion of a SOICR-independent disease mechanism for the G230C mutation. 
However, the cellular impact of this mutation on SOICR is yet to be determined. 
To this end, we generated stable inducible HEK (human embryonic kidney)-293 cell 
lines expressing the RyR2 WT (wild-type) and the G230C mutant. Using single-cell 
Ca2+ imaging, we found that the G230C mutation markedly enhanced the propensity 
for SOICR and reduced the SOICR threshold. Furthermore, the G230C mutation 
increased the sensitivity of single RyR2 channels to both luminal and cytosolic 
Ca2+ activation and the Ca2+-dependent activation of [3H]ryanodine binding. In 
addition, the G230C mutation decreased the thermal stability of the N-terminal 
region (amino acids 1-547) of RyR2. These data suggest that the G230C mutation 
enhances the propensity for SOICR by sensitizing the channel to luminal and 
cytosolic Ca2+ activation, and that G230C has an intrinsic structural impact on 
the N-terminal domains of RyR2.