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Abnormal RyR2 in arrhythmogenic disorders and CICR

Ca 2+ induced Ca 2+ release (CICR) via ryanodine receptor 2 (RyR2) plays a central role in E-C coupling in cardiac cells, i.e., Ca 2+ influx via L-type Ca 2+ channels during action potential (AP) activates RyR2 to release Ca 2+ from the ER and causes muscle contractions. Many arrhythmogenic mutations in RyR2 are reported to increase AP-independent spontaneous Ca 2+ release from ER that often lead to arrhythmia. Two explanations have been proposed for the increased propensity of spontaneous Ca 2+ release: (1) CPVT mutations increase the cytoplasmic Ca 2+ sensitivity of RyR2 to enhance CICR, or (2) mutations decrease threshold for store-overload induced Ca 2+ release (SOICR) by reducing luminal Ca 2+ sensitivity of RyR2. To understand the underlying mechanism for the increased spontaneous Ca 2+ release by the mutations, we performed quantitative evaluation of CICR activity and cytoplasmic and ER Ca 2+ signals in HEK293 cells expressing mutant RyR2s. Furthermore, the effects of RyR2 inhibitors, which had been found by recently established high-throughput screening method, were examined on Ca 2+ signals in RyR2-HEK cells and cardiomyocytes from adult mice. Our results indicate that CICR plays critical role in generation of spontaneous Ca 2+ release and that regulation of CICR is important in suppression of arrhythmia.