The N588K-HERG K+ channel mutation in the 'short QT syndrome':: Mechanism of gain-in-function determined at 37 °C
The N588K-HERG K+ channel mutation in the 'short QT syndrome':: Mechanism of gain-in-function determined at 37 °C
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DOI：
10.1016/j.bbrc.2005.06.112
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发表时间：
2005-08-26
影响因子：
3.1
通讯作者：
Hancox, JC
中科院分区：
文献类型：
--
作者：
McPate, MJ;Duncan, RS;Hancox, JC
特发性短QT综合征（SQTS）的特征是心电图上的QT间期异常短，心律失常和猝死的风险增加。该综合征的一种变体与导致心脏HERG K+通道S5-孔连接区中单个氨基酸变化（N588 K;天冬酰胺变为赖氨酸）的错义突变有关。本研究旨在确定N588 K突变如何在哺乳动物生理温度下改变HERG通道电流（I-HERG）动力学。从中国人卵巢细胞测量的野生型（WT）IHERG的全细胞电流-电压（IV）关系在接近0 mV时最大，并显示出明显的内向整流阳性。相比之下，N588 K I-HERG仅在+60 mV和更正的电压下显示出明显的整流。N588 K-HERG激活的电压依赖性与WT-HERG无显著差异。然而，N588 K IHERG具有比WT I-HERG（-70.05 +/-0.82 mV; P < 0.001，非配对t检验;每种n = 5）显著更高的阳性失活V-0.5（-8.14 +/-0.82 mV）。其P-Na/P-K比值也较大。在动作电位电压钳下，N588 K IHERG的瞬时I-V关系在接近+40 mV时达到峰值，而WT-I-HERG的瞬时I-V关系在接近-37 mV时达到峰值。这些发现强调了S5-P连接体在HERG通道功能中的重要性，并表明N588 K-HERG在生理温度下心室动作电位中较早地增加了复极电流，这是由于I-HERG失活的电压依赖性发生了类似于+60 mV的偏移。(c)2005年爱思唯尔公司All rights reserved.
The idiopathic short QT syndrome (SQTS) is characterised by an abnormally short QT interval on the electrocardiogram and by an increased risk of arrhythmia and sudden death. One variant of the syndrome is linked to missense mutations that lead to a single amino-acid change (N588K; asparagine to lysine) in the S5-Pore linker region of the cardiac HERG K+ channel. This study was performed in order to determine how the N588K mutation alters HERG channel current (I-HERG) kinetics at mammalian physiological temperature. The whole-cell current-voltage (I V) relation for wild-type (WT) IHERG measured from Chinese Hamster Ovary cells was maximal at similar to 0 mV and showed marked inward rectification positive to this. In contrast, N588K I-HERG showed marked rectification only at +60 mV and at more positive voltages. The voltage dependence of activation of N588K-HERG did not differ significantly from that of WT-HERG. However, N588K IHERG had a significantly more positive inactivation V-0.5 (-8.14 +/- 0.82 mV) than did WT I-HERG (-70.05 +/- 0.82 mV; P < 0.001, unpaired t test; n = 5 for each). Its P-Na/P-K ratio was also greater. The instantaneous I-V relation for N588K IHERG under action potential voltage clamp peaked at similar to+40 mV, compared to similar to-37 mV for WT-I-HERG. These findings underscore the importance of the S5-P linker in HERG channel function and indicate that N588K-HERG contributes increased repolarising current earlier in the ventricular action potential at physiological temperature due to a similar to+60 mV shift in voltage dependence of I-HERG inactivation. (c) 2005 Elsevier Inc. All rights reserved.