Li Xiaodong, Zima Aleksey V, Sheikh Farah, Blatter Lothar A, Chen Ju
Department of Medicine, University of California San Diego, La Jolla, CalifA 92093-0641, USA.
Circ Res. 2005 Jun 24;96(12):1274-81. doi: 10.1161/01.RES.0000172556.05576.4c. Epub 2005 Jun 2.
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.
最近的研究表明，肌醇-1,4,5-三磷酸受体（IP3R）介导的Ca2+释放，在心房组织兴奋-收缩偶联（ECC）的调节以及心律失常（特别是慢性心房颤动（AF））的发生中起着重要作用。IP3R 2型（IP3R2）是心房肌细胞中表达的主要IP3R亚型。为了确定IP3R2在心房心律失常发生和ECC中的作用，我们培育了IP3R2基因敲除小鼠。我们的结果显示，内皮素-1（ET-1）刺激野生型（WT）心房肌细胞会导致基础[Ca2+]i升高、动作电位（AP）诱导的[Ca2+]i瞬变增强、ECC效能提高（肌浆网Ca2+释放分数增加），以及由于IP3R依赖性Ca2+释放激活而出现自发性致心律失常性Ca2+释放事件。相比之下，ET-1不会改变IP3R2基因敲除心房肌细胞的舒张期[Ca2+]i，也不会引起自发性Ca2+释放事件。在基础条件下，WT和IP3R2基因敲除心房肌细胞中[Ca2+]i瞬变的时空特性（幅度、上升时间、衰减动力学和空间扩散）以及肌浆网Ca2+释放分数并无差异。WT和IP3R2基因敲除心房肌细胞在异丙肾上腺素刺激下，AP依赖性[Ca2+]i瞬变的幅度和Ca2+火花频率也均显著且非常相似地增加，这表明两种细胞类型均保持强大的变力储备。在WT和IP3R2基因敲除小鼠之间，未检测到Ca2+调节蛋白表达（IP3R1、IP3R3、RyR2、NCX、SERCA2）或心房形态的代偿性变化。这些结果表明，IP3R2的缺失消除了ET-1神经体液刺激的正性变力作用，并使其免受致心律失常作用的影响。
