Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines
Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines
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DOI：
10.1172/jci39027
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发表时间：
2009-09-01
影响因子：
15.9
通讯作者：
Zhang, Shetuan
中科院分区：
文献类型：
--
作者：
Guo, Jun;Massaeli, Hamid;Zhang, Shetuan
虽然激素和药物对离子通道门控的调节已被广泛研究，但对细胞表面离子通道表达水平如何调节知之甚少。在这里，我们证明了在兔体内心脏中，由人ether-a-go-go相关基因（HERG）编码的异源表达的K+通道及其天然对应物快速激活的延迟整流K+通道（I-Kr）的细胞表面密度在生理相关范围内精确地由细胞外K+浓度（[K +]（o））控制。[K +]（o）的减少导致HERG通道在数小时内加速内化和降解。共聚焦分析显示HERG和泛素在HERG内化过程中共定位，在低[K +]（o）条件下过表达泛素促进HERG降解。在内化过程中，HERG通道与多泡体标记物共定位，并且内化的HERG通道靶向溶酶体。我们的研究结果提供了第一个证据，我们的知识，细胞表面密度的电压门控K+通道，HERG，是由生物因子，细胞外K+。由于低钾血症可加重长QT综合征（LQTS）和尖端扭转型室性心动过速，我们的研究结果提供了低钾血症和LQTS之间的潜在机制联系。
Although the modulation of ion channel gating by hormones and drugs has been extensively studied, much less is known about how cell surface ion channel expression levels are regulated. Here, we demonstrate that the cell surface density of both the heterologously expressed K+ channel encoded by the human ether-a-go-go-related gene (HERG) and its native counterpart, the rapidly activating delayed rectifier K+ channel (I-Kr), in rabbit hearts in vivo is precisely controlled by extracellular K+ concentration ([K+](o)) within a physiologically relevant range. Reduction of [K+](o) led to accelerated internalization and degradation of HERG channels within hours. Confocal analysis revealed colocalization between HERG and ubiquitin during the process of HERG internalization, and overexpression of ubiquitin facilitated HERG degradation under low [K+](o). The HERG channels colocalized with a marker of multivesicular bodies during internalization, and the internalized HERG channels were targeted to lysosomes. Our results provide the first evidence to our knowledge that the cell surface density of a voltage-gated K+ channel, HERG, is regulated by a biological factor, extracellular K+. Because hypokalemia is known to exacerbate long QT syndrome (LQTS) and Torsades de pointes tachyarrhythmias, our findings provide a potential mechanistic link between hypokalemia and LQTS.