Published online before print June 2, 2005, doi: 10.1161/01.RES.0000172556.05576.4c
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© 2005 American Heart Association, Inc.
Cellular Biology |
Endothelin-1–Induced Arrhythmogenic Ca2+ Signaling Is Abolished in Atrial Myocytes of Inositol-1,4,5-Trisphosphate(IP3)–Receptor Type 2–Deficient Mice
From the Department of Medicine (H.L., F.S., J.C.), University of California San Diego, La Jolla, Calif; and the Department of Physiology (A.V.Z., L.A.B.), Loyola University of Chicago, Stritch School of Medicine, Maywood, Ill.
Correspondence to Ju Chen, Department of Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0641. E-mail juchen{at}ucsd.edu
Recent studies have suggested that inositol-1,4,5-trisphosphate-receptor (IP3R)–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). 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 [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 IP3R-dependent Ca2+ release. In contrast, ET-1 did not alter diastolic [Ca2+]i or cause spontaneous Ca2+ release events in IP3R2-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 IP3R2-deficient atrial myocytes. WT and IP3R2-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 (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.
Key Words: IP3 receptor • intracellular calcium • atrial arrhythmias • excitation-contraction coupling • endothelin
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