KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders.
KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders.
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DOI：
10.1016/j.hrthm.2009.10.012
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发表时间：
2010
期刊：
影响因子：
5.5
通讯作者：
Horie, Minoru
中科院分区：
文献类型：
--
作者：
Wu, Jie;Shimizu, Wataru;Ding, Wei-Guang;Ohno, Seiko;Toyoda, Futoshi;Itoh, Hideki;Zang, Wei-Jin;Miyamoto, Yoshihiro;Kamakura, Shiro;Matsuura, Hiroshi;Nademanee, Koonlawee;Brugada, Josep;Brugada, Pedro;Brugada, Ramon;Vatta, Matteo;Towbin, Jeffrey A.;Antzelevitch, Charles;Horie, Minoru
瞬时外向电流Ito在动作电位的极早期阶段调节心肌电特性方面至关重要。辅助β亚基KCNE2最近被证明调节Ito。本研究的目的是检查KCNE2及其两个已发表的变体（M54T，I57T）对伊藤的贡献。采用膜片钳技术研究了Kv4.3（人Ito α亚基）与野生型（WT）、M54 T和I57 T KCNE2在异源细胞系中表达的功能相互作用。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，使稳态失活曲线的电压依赖性正移。这些修饰使得Kv4.3通道更类似于天然心脏Ito。与WT KCNE2相比，M54T和I57T变体均显著增加Ito电流密度并减慢失活速率。此外，这两种变体都加速了从失活中恢复。研究结果表明，KCNE2在人类心脏天然Ito通道复合物的正常功能中起着关键作用，并且M54T和I57T变体导致Ito功能的获得，这可能有助于产生潜在的心律失常和遗传性致死性心律失常的发病机制。
The transient outward current Ito is of critical importance in regulating myocardial electrical properties during the very early phase of the action potential. The auxiliary β subunit KCNE2 recently was shown to modulate Ito. The purpose of this study was to examine the contributions of KCNE2 and its two published variants (M54T, I57T) to Ito. The functional interaction between Kv4.3 (α subunit of human Ito) 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 Ito. Both M54T and I57T variants significantly increased Ito 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 Ito channel complex in human heart and that M54T and I57T variants lead to a gain of function of Ito, which may contribute to generating potential arrhythmogeneity and pathogenesis for inherited fatal rhythm disorders.
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