Long QT syndrome-associated mutations in the Per-Arnt-Sim (PAS) domain of HERG potassium channels accelerate channel deactivation
Long QT syndrome-associated mutations in the Per-Arnt-Sim (PAS) domain of HERG potassium channels accelerate channel deactivation
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DOI：
10.1074/jbc.274.15.10113
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发表时间：
1999-04-09
影响因子：
4.8
通讯作者：
Sanguinetti, MC
中科院分区：
文献类型：
--
作者：
Chen, J;Zou, AR;Sanguinetti, MC
人类ether-a-go-go相关基因（HERG）的突变导致长QT综合征，这是一种遗传性心脏复极障碍，使受影响的个体易于发生危及生命的心律失常。HERG编码心脏快速延迟整流钾通道，介导心室动作电位的复极。在这项研究中，我们使用卵母细胞表达系统和电压钳技术来确定位于HERG氨基端区域的八个长QT综合征相关突变的功能后果（F29 L、N33 T、G53 R、R56 Q、C66 G、H70 R、A78 P和L 86 R），当在卵母细胞中单独表达时，突变亚基形成具有改变的门控特性的功能通道，所有突变都会加速失活。一些突变体将通道可用性的电压依赖性转移到更正的电位。电压斜坡表明突变通道的快速失活将减少心脏动作电位复极阶段的外向电流，并导致校正QT间期QT（c）延长。HERG的氨基端区域最近结晶并显示具有Per-S-Sim（PAS）结构域。这些突变的位置表明它们可能破坏PAS结构域并干扰其与HERG通道的S4-S5接头的相互作用。
Mutations in the human ether-a-go-go-related gene (HERG) cause long QT syndrome, an inherited disorder of cardiac repolarization that predisposes affected individuals to life-threatening arrhythmias, HERG encodes the cardiac rapid delayed rectifier potassium channel that mediates repolarization of ventricular action potentials. In this study, we used the oocyte expression system and voltage clamp techniques to determine the functional consequences of eight long QT syndrome-associated mutations located in the amino-terminal region of HERG (F29L, N33T, G53R, R56Q, C66G, H70R, A78P, and L86R), Mutant subunits formed functional channels with altered gating properties when expressed alone in oocytes, Deactivation was accelerated by all mutations. Some mutants shifted the voltage dependence of channel availability to more positive potentials. Voltage ramps indicated that fast deactivation of mutant channels would reduce outward current during the repolarization phase of the cardiac action potential and cause prolongation of the corrected QT interval, QT(c), The amino-terminal region of HERG was recently crystallized and shown to possess a Per-Amt-Sim (PAS) domain. The location of these mutations suggests they may disrupt the PAS domain and interfere with its interaction with the S4-S5 linker of the HERG channel.