The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
PLoS One. 2010 Feb 2;5(2):e9021. doi: 10.1371/journal.pone.0009021.
The repolarizing cardiac rapid delayed rectifier current, I(Kr), is composed of ERG1 channels. It has been suggested that two isoforms of the ERG1 protein, ERG1a and ERG1b, both contribute to I(Kr). Marked heterogeneity in the kinetic properties of native I(Kr) has been described. We hypothesized that the heterogeneity of native I(Kr) can be reproduced by differential expression of ERG1a and ERG1b isoforms. Furthermore, the functional consequences of differential expression of ERG1 isoforms were explored as a potential mechanism underlying native heterogeneity of action potential duration (APD) and restitution.
METHODOLOGY/PRINCIPAL FINDINGS: The results show that the heterogeneity of native I(Kr) can be reproduced in heterologous expression systems by differential expression of ERG1a and ERG1b isoforms. Characterization of the macroscopic kinetics of ERG1 currents demonstrated that these were dependent on the relative abundance of ERG1a and ERG1b. Furthermore, we used a computational model of the ventricular cardiomyocyte to show that both APD and the slope of the restitution curve may be modulated by varying the relative abundance of ERG1a and ERG1b. As the relative abundance of ERG1b was increased, APD was gradually shortened and the slope of the restitution curve was decreased.
CONCLUSIONS/SIGNIFICANCE: Our results show that differential expression of ERG1 isoforms may explain regional heterogeneity of I(Kr) kinetics. The data demonstrate that subunit dependent changes in channel kinetics are important for the functional properties of ERG1 currents and hence I(Kr). Importantly, our results suggest that regional differences in the relative abundance of ERG1 isoforms may represent a potential mechanism underlying the heterogeneity of both APD and APD restitution observed in mammalian hearts.
复极化心脏快速延迟整流电流 I(Kr) 由 ERG1 通道组成。有人提出，ERG1 蛋白的两种同工型 ERG1a 和 ERG1b 都有助于 I(Kr)。已经描述了天然 I(Kr)的动力学特性存在明显的异质性。我们假设，通过 ERG1a 和 ERG1b 同工型的差异表达，可以再现天然 I(Kr)的异质性。此外，还探讨了 ERG1 同工型差异表达的功能后果，作为动作电位时程 (APD) 和恢复性内在异质性的潜在机制。
方法/主要发现：结果表明，通过 ERG1a 和 ERG1b 同工型的差异表达，可以在异源表达系统中再现天然 I(Kr)的异质性。ERG1 电流的宏观动力学特性的表征表明，这些特性依赖于 ERG1a 和 ERG1b 的相对丰度。此外，我们使用心室肌细胞的计算模型表明，APD 和恢复性曲线的斜率都可以通过改变 ERG1a 和 ERG1b 的相对丰度来调节。随着 ERG1b 相对丰度的增加，APD 逐渐缩短，恢复性曲线的斜率降低。
结论/意义：我们的结果表明，ERG1 同工型的差异表达可能解释了 I(Kr)动力学的区域异质性。数据表明，通道动力学的亚基依赖性变化对于 ERG1 电流的功能特性，即 I(Kr)很重要。重要的是，我们的结果表明，ERG1 同工型相对丰度的区域差异可能是哺乳动物心脏中观察到的 APD 和 APD 恢复性异质性的潜在机制。
