Modulation of KCNQ1 alternative splicing regulates cardiac IKs and action potential repolarization.
Modulation of KCNQ1 alternative splicing regulates cardiac IKs and action potential repolarization.
复制标题
DOI：
10.1016/j.hrthm.2013.04.014
复制
发表时间：
2013-08
期刊：
影响因子：
5.5
通讯作者：
Cui, Jianmin
中科院分区：
文献类型：
--
作者：
Lee, Hsiang-Chun;Rudy, Yoram;Po-Yuan;Sheu, Sheng-Hsiung;Chang, Jan-Gowth;Cui, Jianmin
IKs通道由成孔KCNQ 1和辅助KCNE 1亚基组成，在决定心肌细胞动作电位时程（APD）中起关键作用。药物诱导的KCNQ 1剪接改变的后果仍然未知。我们研究了阿米洛利对KCNQ 1选择性剪接的调节以及由此引起的心室肌细胞IKs和动作电位（AP）的变化。分离犬内膜、中层心肌和心外膜心室肌细胞。RT-PCR和Western blot检测KCNQ 1a和KCNQ 1b以及一系列剪接因子的表达水平。阿米洛利诱导的KCNQ 1b/总KCNQ 1比值的改变对AP的影响，采用全细胞膜片钳测量，有和无异丙肾上腺素。50 μmol/L阿米洛利作用6小时，KCNQ 1a在中层心肌细胞中的转录和翻译水平增加，但在心内膜和心外膜心肌细胞中减少。中层心肌细胞剪接因子的变化与心内膜和心外膜心肌细胞相反。在中层心肌细胞，阿米洛利显著缩短APD，减少异丙肾上腺素诱导的早期后除极。在β-肾上腺素能刺激下，使用人心室肌细胞模型进行动作电位模拟，证实了相同的阿米洛利诱导作用。此外，阿米洛利减少跨室壁复极离散伪心电图。阿米洛利通过调节KCNQ 1剪接来调节跨壁差异的IKs和动作电位，并降低细胞的发生率。我们认为KCNQ 1剪接的调节可能有助于预防心律失常。
IKs channels, made of the pore-forming KCNQ1 and auxiliary KCNE1 subunits, play a key role in determining action potential duration (APD) in cardiac myocytes. The consequences of drug-induced KCNQ1 splice alteration remain unknown. We study the modulation of KCNQ1 alternative splicing by amiloride and the consequent changes in IKs and action potentials (AP) in ventricular myocytes. Canine endocardial, midmyocardial, and epicardial ventricular myocytes were isolated. Levels of KCNQ1a and KCNQ1b as well as a series of splicing factors were quantified by RT-PCR and Western blot. The impact of amiloride-induced alterations in KCNQ1b/total KCNQ1 ratio on AP was measured using whole-cell patch clamp with and without isoproterenol. With 50 µmol/L amiloride for 6 hours, KCNQ1a at transcriptional and translational levels increased in midmyocardial but decreased in endo- and epicardial myocytes. Likewise, changes of splicing factors in midmyocardial were opposite to that in endo- and epicardial myocytes. In midmyocardial myocytes amiloride shortened APD and decreased isoproterenol-induced early afterdepolarizations significantly. The same amiloride-induced effects were demonstrated by using human ventricular myocyte model for action potentials simulations under β-adrenergic stimulation. Moreover, amiloride reduced the transmural dispersion of repolarization in pseudo-ECG. Amiloride regulates IKs and action potentials with transmural differences and reduces arrhythmogenecity through modulating KCNQ1 splicing. We suggested that modulation of KCNQ1 splicing may help prevent arrhythmia.
登录
查看更多内容
影响因子：
37.8
作者：
Crotti, Lia;Monti, Maria Cristina;George, Alfred L., Jr.
通讯作者：
George, Alfred L., Jr.
DOI：
10.1046/j.1540-8167.2002.00172.x
发表时间：
2002-02-01
影响因子：
2.7
作者：
Burashnikov, A;Antzelevitch, C
通讯作者：
Antzelevitch, C
影响因子：
2.8
作者：
Molnar, J;Rosenthal, JE;Somberg, JC
通讯作者：
Somberg, JC
影响因子：
3.7
作者：
Chang JG;Yang DM;Chang WH;Chow LP;Chan WL;Lin HH;Huang HD;Chang YS;Hung CH;Yang WK
通讯作者：
Yang WK
影响因子：
39.3
作者：
Amin AS;Giudicessi JR;Tijsen AJ;Spanjaart AM;Reckman YJ;Klemens CA;Tanck MW;Kapplinger JD;Hofman N;Sinner MF;Müller M;Wijnen WJ;Tan HL;Bezzina CR;Creemers EE;Wilde AA;Ackerman MJ;Pinto YM
通讯作者：
Pinto YM