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Circulation Research. 2005
Published online before print June 2, 2005, doi: 10.1161/01.RES.0000172556.05576.4c
A more recent version of this article appeared on June 24, 2005
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Right arrow Arrythmias-basic studies
Right arrow Calcium cycling/excitation-contraction coupling

Submitted on March 8, 2005
Revised on May 11, 2005
Accepted on May 24, 2005

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

Xiaodong Li ; Aleksey V. Zima ; Farah Sheikh ; Lothar A. Blatter ; and Ju Chen *

From the Department of Medicine (H.L., F.S., J.C.), University of California San Diego, La Jolla; the Department of Physiology (A.V.Z., L.A.B.), Loyola University of Chicago, Stritch School of Medicine, Maywood, Ill.

* To whom correspondence should be addressed. 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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