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Recent studies have suggested that inositol-1,4,5-trisphosphate-receptor (IP3 R)–mediated Ca2+ 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). IP3 R type-2 (IP3 R2) is the predominant IP3 R isoform expressed in atrial myocytes. To determine the role of IP3 R2 in atrial arrhythmogenesis and ECC, we generated IP3 R2-deficient mice. Our results revealed that endothelin-1 (ET-1) stimulation of wild-type (WT) atrial myocytes caused an increase in basal [Ca2+ ]i , an enhancement of action potential (AP)-induced [Ca2+ ]i transients, an improvement of the efficacy of ECC (increased fractional SR Ca2+ release), and the occurrence of spontaneous arrhythmogenic Ca2+ release events as the result of activation of IP3 R-dependent Ca2+ release. In contrast, ET-1 did not alter diastolic [Ca2+ ]i or cause spontaneous Ca2+ release events in IP3 R2-deficient atrial myocytes. Under basal conditions the spatio-temporal properties (amplitude, rise-time, decay kinetics, and spatial spread) of [Ca2+ ]i transients and fractional SR Ca2+ release were not different in WT and IP3 R2-deficient atrial myocytes. WT and IP3 R2-deficient atrial myocytes also showed a significant and very similar increase in the amplitude of AP-dependent [Ca2+ ]i transients and Ca2+ spark frequency in response to isoproterenol stimulation, suggesting that both cell types maintained a strong inotropic reserve. No compensatory changes in Ca2+ regulatory protein expression (IP3 R1, IP3 R3, RyR2, NCX, SERCA2) or morphology of the atria could be detected between WT and IP3 R2-deficient mice. These results show that lack of IP3 R2 abolishes the positive inotropic effect of neurohumoral stimulation with ET-1 and protects from its arrhythmogenic effects.

circulation research

Endothelin-1–Induced Arrhythmogenic Ca <sup>2+</sup> Signaling Is Abolished in Atrial Myocytes of Inositol-1,4,5-Trisphosphate(IP <sub>3</sub> )–Receptor Type 2–Deficient Mice

Endothelin-1–Induced Arrhythmogenic Ca 2+ Signaling Is Abolished in Atrial Myocytes of Inositol-1,4,5-Trisphosphate(IP 3 )–Receptor Type 2–Deficient Mice

Endothelin-1–Induced Arrhythmogenic Ca ²⁺ Signaling Is Abolished in Atrial Myocytes of Inositol-1,4,5-Trisphosphate(IP ₃ )–Receptor Type 2–Deficient Mice