Pharmacology Department, Medical School of Xi'an Jiaotong University. Xi'an, Shaanxi, China.
Heart Rhythm. 2010;7(2):199-205. doi: 10.1016/j.hrthm.2009.10.012. Epub 2009 Oct 12.
The transient outward current I(to) is of critical importance in regulating myocardial electrical properties during the very early phase of the action potential. The auxiliary beta subunit KCNE2 recently was shown to modulate I(to).
The purpose of this study was to examine the contributions of KCNE2 and its two published variants (M54T, I57T) to I(to).
The functional interaction between Kv4.3 (alpha subunit of human I(to)) and wild-type (WT), M54T, and I57T KCNE2, expressed in a heterologous cell line, was studied using patch-clamp techniques.
Compared to expression of Kv4.3 alone, co-expression of WT KCNE2 significantly reduced peak current density, slowed the rate of inactivation, and caused a positive shift of voltage dependence of steady-state inactivation curve. These modifications rendered Kv4.3 channels more similar to native cardiac I(to). Both M54T and I57T variants significantly increased I(to) current density and slowed the inactivation rate compared with WT KCNE2. Moreover, both variants accelerated the recovery from inactivation.
The study results suggest that KCNE2 plays a critical role in the normal function of the native I(to) channel complex in human heart and that M54T and I57T variants lead to a gain of function of I(to), which may contribute to generating potential arrhythmogeneity and pathogenesis for inherited fatal rhythm disorders.
瞬时外向电流 I(to) 在动作电位的早期阶段对调节心肌电生理特性至关重要。辅助β亚基 KCNE2 最近被证明可以调节 I(to)。
本研究旨在探讨 KCNE2 及其两个已发表的变体（M54T、I57T）对 I(to) 的贡献。
使用膜片钳技术研究 Kv4.3（人类 I(to)的α亚基）与野生型（WT）、M54T 和 I57T KCNE2 在异源细胞系中的功能相互作用。
与单独表达 Kv4.3 相比，共表达 WT KCNE2 显著降低了峰值电流密度，减慢了失活速率，并导致稳态失活曲线的电压依赖性发生正移。这些修饰使 Kv4.3 通道更类似于天然心脏 I(to)。与 WT KCNE2 相比，M54T 和 I57T 变体均显著增加了 I(to)电流密度并减慢了失活速率。此外，两种变体均加速了失活后的恢复。
研究结果表明，KCNE2 在人类心脏天然 I(to)通道复合物的正常功能中起着关键作用，而 M54T 和 I57T 变体导致 I(to)功能获得，这可能导致潜在的心律失常和遗传性致命节律紊乱的发病机制。
