Déri Szilvia, Hartai Teodóra, Virág László, Jost Norbert, Labro Alain J, Varró András, Baczkó István, Nattel Stanley, Ördög Balázs
Department of Pharmacology and Pharmacotherapy, University of Szeged, 6720 Szeged, Hungary.
ELKH-SZTE Research Group for Cardiovascular Pharmacology, 6720 Szeged, Hungary.
Pharmaceuticals (Basel). 2022 Dec 13;15(12):1550. doi: 10.3390/ph15121550.
Long QT syndrome (LQTS) is an inherited cardiac rhythm disorder associated with increased incidence of cardiac arrhythmias and sudden death. LQTS type 5 (LQT5) is caused by dominant mutant variants of KCNE1, a regulatory subunit of the voltage-gated ion channels generating the cardiac potassium current I. While mutant LQT5 KCNE1 variants are known to inhibit I amplitudes in heterologous expression systems, cardiomyocytes from a transgenic rabbit LQT5 model displayed unchanged I amplitudes, pointing towards the critical role of additional factors in the development of the LQT5 phenotype in vivo. In this study, we demonstrate that KCNE3, a candidate regulatory subunit of I channels minimizes the inhibitory effects of LQT5 KCNE1 variants on I amplitudes, while current deactivation is accelerated. Such changes recapitulate I properties observed in LQT5 transgenic rabbits. We show that KCNE3 accomplishes this by displacing the KCNE1 subunit within the I ion channel complex, as evidenced by a dedicated biophysical assay. These findings depict KCNE3 as an integral part of the I channel complex that regulates I function in cardiomyocytes and modifies the development of the LQT5 phenotype.
长QT综合征（LQTS）是一种遗传性心律失常疾病，与心律失常和猝死的发生率增加有关。5型长QT综合征（LQT5）由KCNE1的显性突变变体引起，KCNE1是产生心脏钾电流I的电压门控离子通道的调节亚基。虽然已知突变的LQT5 KCNE1变体在异源表达系统中会抑制I的幅度，但来自转基因兔LQT5模型的心肌细胞显示I的幅度未改变，这表明其他因素在体内LQT5表型发展中起关键作用。在本研究中，我们证明I通道的候选调节亚基KCNE3可将LQT5 KCNE1变体对I幅度的抑制作用降至最低，同时加速电流失活。这些变化重现了在LQT5转基因兔中观察到的I特性。我们表明，KCNE3通过在I离子通道复合物中取代KCNE1亚基来实现这一点，这通过专门的生物物理测定得到证明。这些发现表明KCNE3是I通道复合物的一个组成部分，它调节心肌细胞中的I功能并改变LQT5表型的发展。
