Mechanistic basis for type 2 long QT syndrome caused by KCNH2 mutations that disrupt conserved arginine residues in the voltage sensor.
Mechanistic basis for type 2 long QT syndrome caused by KCNH2 mutations that disrupt conserved arginine residues in the voltage sensor.
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DOI：
10.1007/s00232-013-9539-6
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发表时间：
2013-05
影响因子：
2.4
通讯作者：
Delisle, Brian P.
中科院分区：
文献类型：
--
作者：
McBride, Christie M.;Smith, Ashley M.;Smith, Jennifer L.;Reloj, Allison R.;Velasco, Ellyn J.;Powell, Jonathan;Elayi, Claude S.;Bartos, Daniel C.;Burgess, Don E.;Delisle, Brian P.
KCNH2编码Kv11.1通道，该通道在心脏中传导快速激活的延迟整流钾电流（IKr）。KCNH2突变导致2型长QT综合征（LQT2），这增加了危及生命的室性心律失常的风险。预测LQT2突变通过在复极期间降低IKr来延长心脏动作电位（AP）。Kv11.1在电压传感器的第四跨膜区段（S4）中含有几个保守的碱性氨基酸，其对于正常通道运输和门控是重要的。本研究旨在确定S4中保守精氨酸残基（R531Q、R531W或R534L）的LQT 2突变改变Kv11.1功能的机制。瞬时表达R531Q、R531W或R534L的HEK293细胞的Western印迹分析表明，只有R534L抑制Kv11.1运输。电压钳实验表明，R531Q或R531W显着改变Kv11.1电流（IKv11.1）的激活，失活，失活和失活的恢复。野生型的共表达（模拟患者的基因型）主要纠正IKv11.1激活和失活的变化，但失活动力学仍然更快。使用人类心室AP模型的计算模拟表明，加速失活速率足以延长AP，但与简单地降低IKr相比，这些影响很小。这些是第一个数据证明，共表达野生型可以纠正激活和失活功能障碍所造成的突变在一个关键的电压敏感残基Kv11.1。我们的结论是，一些Kv11.1突变可能会加速失活，导致LQT2，但心室AP持续时间是更敏感的突变，降低IKr。这可能解释了为什么大多数LQT2突变是无意义的或运输缺陷的。
KCNH2 encodes the Kv11.1 channel, which conducts the rapidly activating delayed rectifier K+ current (IKr) in the heart. KCNH2 mutations cause type 2 long QT syndrome (LQT2), which increases the risk for life-threatening ventricular arrhythmias. LQT2 mutations are predicted to prolong the cardiac action potential (AP) by reducing IKr during repolarization. Kv11.1 contains several conserved basic amino acids in the fourth transmembrane segment (S4) of the voltage sensor that are important for normal channel trafficking and gating. This study sought to determine the mechanism(s) by which LQT2 mutations at conserved arginine residues in S4 (R531Q, R531W or R534L) alter Kv11.1 function. Western blot analyses of HEK293 cells transiently expressing R531Q, R531W or R534L suggested that only R534L inhibited Kv11.1 trafficking. Voltage-clamping experiments showed that R531Q or R531W dramatically altered Kv11.1 current (IKv11.1) activation, inactivation, recovery from inactivation and deactivation. Coexpression of wild type (to mimic the patients’ genotypes) mostly corrected the changes in IKv11.1 activation and inactivation, but deactivation kinetics were still faster. Computational simulations using a human ventricular AP model showed that accelerating deactivation rates was sufficient to prolong the AP, but these effects were minimal compared to simply reducing IKr. These are the first data to demonstrate that coexpressing wild type can correct activation and inactivation dysfunction caused by mutations at a critical voltage-sensing residue in Kv11.1. We conclude that some Kv11.1 mutations might accelerate deactivation to cause LQT2 but that the ventricular AP duration is much more sensitive to mutations that decrease IKr. This likely explains why most LQT2 mutations are nonsense or trafficking-deficient.
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