Endothelin-1–Induced Arrhythmogenic Ca2+ Signaling Is Abolished in Atrial Myocytes of Inositol-1,4,5-Trisphosphate(IP3)–Receptor Type 2–Deficient Mice

Recent studies have suggested that inositol-1,4,5-trisphosphate-receptor (IP3R)–mediated Ca release plays an important role in the modulation of excitation–contraction coupling (ECC) in atrial tissue and the generation of arrhythmias, specifically chronic atrial fibrillation (AF). IP3R type-2 (IP3R2) is the predominant IP3R isoform expressed in atrial myocytes. To determine the role of IP3R2 in atrial arrhythmogenesis and ECC, we generated IP3R2-deficient mice. Our results revealed that endothelin-1 (ET-1) stimulation of wild-type (WT) atrial myocytes caused an increase in basal [Ca]i, an enhancement of action potential (AP)-induced [Ca]i transients, an improvement of the efficacy of ECC (increased fractional SR Ca release), and the occurrence of spontaneous arrhythmogenic Ca release events as the result of activation of IP3R-dependent Ca release. In contrast, ET-1 did not alter diastolic [Ca]i or cause spontaneous Ca release events in IP3R2-deficient atrial myocytes. Under basal conditions the spatio-temporal properties (amplitude, rise-time, decay kinetics, and spatial spread) of [Ca]i transients and fractional SR Ca release were not different in WT and IP3R2-deficient atrial myocytes. WT and IP3R2-deficient atrial myocytes also showed a significant and very similar increase in the amplitude of AP-dependent [Ca]i transients and Ca spark frequency in response to isoproterenol stimulation, suggesting that both cell types maintained a strong inotropic reserve. No compensatory changes in Ca regulatory protein expression (IP3R1, IP3R3, RyR2, NCX, SERCA2) or morphology of the atria could be detected between WT and IP3R2-deficient mice. These results show that lack of IP3R2 abolishes the positive inotropic effect of neurohumoral stimulation with ET-1 and protects from its arrhythmogenic effects.