TWIK-1 Two-Pore Domain Potassium Channels Change Ion Selectivity and Conduct Inward Leak Sodium Currents in Hypokalemia
TWIK-1 Two-Pore Domain Potassium Channels Change Ion Selectivity and Conduct Inward Leak Sodium Currents in Hypokalemia
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DOI：
10.1126/scisignal.2001726
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发表时间：
2011-06-07
影响因子：
7.3
通讯作者：
Chen, Haijun
中科院分区：
文献类型：
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作者：
Ma, Liqun;Zhang, Xuexin;Chen, Haijun
背景钾(K+)通道通常对K+具有选择性通透性，可将心脏静息膜电位维持在-80 mV左右。在病理性低钾血症的亚生理性细胞外K+浓度([K+](O))中，人心肌细胞的静息膜电位可去极化至-50 mV左右，而大鼠和小鼠心肌细胞则超极化，符合K+的Nernst方程。心肌细胞在亚生理性[K+](O)中的这种矛盾的去极化，可能导致心律失常，被认为涉及到内漏钠(Na+)电流。在这里，我们展示了人类心脏twik-1(也称为K2P1)双孔结构域K+通道改变了离子选择性，使其对外部Na+具有通透性，并在亚生理[K+](O)中传导向内泄漏的Na+电流。这种改变的离子选择性需要孔选择性序列TxGYG中的特定苏氨酸残基(Thr(118))。小鼠心肌细胞来源的HL-1细胞表现出反常去极化，并异位表达twik-1通道，而人球形原代心肌细胞中的twik-1基因敲除消除了反常去极化。这些结果表明，在病理性低钾血症过程中，Twik-1 K+通道的离子选择性发生改变，阐明了[K+](O)降低时触发或促进心脏反常去极化的内漏Na+电流的分子基础，并确定了调节心脏兴奋性的机制。
Background potassium (K+) channels, which are normally selectively permeable to K+, maintain the cardiac resting membrane potential at around -80 mV. In subphysiological extracellular K+ concentrations ([K+](o)), which occur in pathological hypokalemia, the resting membrane potential of human cardiomyocytes can depolarize to around -50 mV, whereas rat and mouse cardiomyocytes become hyperpolarized, consistent with the Nernst equation for K+. This paradoxical depolarization of cardiomyocytes in subphysiological [K+](o), which may contribute to cardiac arrhythmias, is thought to involve an inward leak sodium (Na+) current. Here, we show that human cardiac TWIK-1 (also known as K2P1) two-pore domain K+ channels change ion selectivity, becoming permeable to external Na+, and conduct inward leak Na+ currents in subphysiological [K+](o). A specific threonine residue (Thr(118)) within the pore selectivity sequence TxGYG was required for this altered ion selectivity. Mouse cardiomyocyte-derived HL-1 cells exhibited paradoxical depolarization with ectopic expression of TWIK-1 channels, whereas TWIK-1 knockdown in human spherical primary cardiac myocytes eliminated paradoxical depolarization. These findings indicate that ion selectivity of TWIK-1 K+ channels changes during pathological hypokalemia, elucidate a molecular basis for inward leak Na+ currents that could trigger or contribute to cardiac paradoxical depolarization in lowered [K+](o), and identify a mechanism for regulating cardiac excitability.