Overexpression of the Large-Conductance, Ca2+-Activated K+ (BK) Channel Shortens Action Potential Duration in HL-1 Cardiomyocytes.
Overexpression of the Large-Conductance, Ca2+-Activated K+ (BK) Channel Shortens Action Potential Duration in HL-1 Cardiomyocytes.
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DOI：
10.1371/journal.pone.0130588
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Rhee SW
中科院分区：
文献类型：
--
作者：
Stimers JR;Song L;Rusch NJ;Rhee SW
长QT综合征的特征是心电图上Q波和T波之间的间期延长。这种异常反映了一些基因突变或多种药物导致的心室动作电位延长。由于目前尚无有效的治疗方法，我们探索了利用大电导、钙激活的K+(BK)通道来缩短动作电位时程的可能性。我们推测，在HL-1细胞中表达人BK通道的致孔α亚单位(HBKα)可以缩短该小鼠心房细胞系的动作电位时程。Hbkα的表达对其他离子通道的表达水平影响很小，但Kv11.1的表达水平略有下降。膜片钳制表达hBKα的HL-1细胞呈现外向电压和钙敏感的K+电流，该电流可被BK通道阻断剂iberiooxin(100 NM)所抑制。这种BK电流表型在未转染的HL-1细胞和假转染空载体的HL-1缺失细胞中均未检测到。重要的是，表达HBKα的HL-1细胞的时程平均为14.3±2.8ms(n=10)，与不表达BKα的HL-1细胞相比，时程缩短了53%。后者平均时程为31.0±5.1ms(n=13)。表达HBKα的细胞的动作电位时程缩短可被100 nM硫代巴比妥钠毒素恢复到正常时程，提示BK通道的复极化K+电流是动作电位缩短的原因。这些发现提供了初步的概念证据，即将HBKα通道引入心肌细胞系可以缩短APD值，并提高了基于基因的干预增加心肌细胞中HBKα通道作为长QT综合征的治疗策略的可能性。
Long QT syndrome is characterized by a prolongation of the interval between the Q wave and the T wave on the electrocardiogram. This abnormality reflects a prolongation of the ventricular action potential caused by a number of genetic mutations or a variety of drugs. Since effective treatments are unavailable, we explored the possibility of using cardiac expression of the large-conductance, Ca2+-activated K+ (BK) channel to shorten action potential duration (APD). We hypothesized that expression of the pore-forming α subunit of human BK channels (hBKα) in HL-1 cells would shorten action potential duration in this mouse atrial cell line. Expression of hBKα had minimal effects on expression levels of other ion channels with the exception of a small but significant reduction in Kv11.1. Patch-clamped hBKα expressing HL-1 cells exhibited an outward voltage- and Ca2+-sensitive K+ current, which was inhibited by the BK channel blocker iberiotoxin (100 nM). This BK current phenotype was not detected in untransfected HL-1 cells or in HL-1 null cells sham-transfected with an empty vector. Importantly, APD in hBKα-expressing HL-1 cells averaged 14.3 ± 2.8 ms (n = 10), which represented a 53% reduction in APD compared to HL-1 null cells lacking BKα expression. APD in the latter cells averaged 31.0 ± 5.1 ms (n = 13). The shortened APD in hBKα-expressing cells was restored to normal duration by 100 nM iberiotoxin, suggesting that a repolarizing K+ current attributed to BK channels accounted for action potential shortening. These findings provide initial proof-of-concept that the introduction of hBKα channels into a cardiac cell line can shorten APD, and raise the possibility that gene-based interventions to increase hBKα channels in cardiac cells may hold promise as a therapeutic strategy for long QT syndrome.
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影响因子：
7.4
作者：
Hu, Xiang-Qun;Zhang, Lubo
通讯作者：
Zhang, Lubo
DOI：
10.1161/circep.111.962019
发表时间：
2012-08-01
期刊：
Circulation. Arrhythmia and electrophysiology
影响因子：
--
作者：
Schwartz PJ;Crotti L;Insolia R
通讯作者：
Insolia R
影响因子：
5.6
作者：
Li, Wei;Gao, Shang-Bang;Xu, Tao
通讯作者：
Xu, Tao
影响因子：
4.5
作者：
Rhee, SW;Starr, T;Storrie, B
通讯作者：
Storrie, B
影响因子：
4.8
作者：
Brenner, R;Jegla, TJ;Aldrich, RW
通讯作者：
Aldrich, RW