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

Abstract

Recent studies have suggested that inositol-1,4,5-trisphosphate-receptor (IP 3 R)–mediated Ca 2+ 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). IP 3 R type-2 (IP 3 R2) is the predominant IP 3 R isoform expressed in atrial myocytes. To determine the role of IP 3 R2 in atrial arrhythmogenesis and ECC, we generated IP 3 R2-deficient mice. Our results revealed that endothelin-1 (ET-1) stimulation of wild-type (WT) atrial myocytes caused an increase in basal [Ca 2+ ] i , an enhancement of action potential (AP)-induced [Ca 2+ ] i transients, an improvement of the efficacy of ECC (increased fractional SR Ca 2+ release), and the occurrence of spontaneous arrhythmogenic Ca 2+ release events as the result of activation of IP 3 R-dependent Ca 2+ release. In contrast, ET-1 did not alter diastolic [Ca 2+ ] i or cause spontaneous Ca 2+ release events in IP 3 R2-deficient atrial myocytes. Under basal conditions the spatio-temporal properties (amplitude, rise-time, decay kinetics, and spatial spread) of [Ca 2+ ] i transients and fractional SR Ca 2+ release were not different in WT and IP 3 R2-deficient atrial myocytes. WT and IP 3 R2-deficient atrial myocytes also showed a significant and very similar increase in the amplitude of AP-dependent [Ca 2+ ] i transients and Ca 2+ spark frequency in response to isoproterenol stimulation, suggesting that both cell types maintained a strong inotropic reserve. No compensatory changes in Ca 2+ regulatory protein expression (IP 3 R1, IP 3 R3, RyR2, NCX, SERCA2) or morphology of the atria could be detected between WT and IP 3 R2-deficient mice. These results show that lack of IP 3 R2 abolishes the positive inotropic effect of neurohumoral stimulation with ET-1 and protects from its arrhythmogenic effects.