Chen J, Zou A, Splawski I, Keating M T, Sanguinetti M C
Department of Medicine, Division of Cardiology, University of Utah, Salt Lake City, Utah 84112, USA.
J Biol Chem. 1999 Apr 9;274(15):10113-8. doi: 10.1074/jbc.274.15.10113.
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, QTc. The amino-terminal region of HERG was recently crystallized and shown to possess a Per-Arnt-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.
人类醚 - 去极化相关基因（HERG）的突变会导致长QT综合征，这是一种遗传性心脏复极化障碍疾病，使受影响个体易患危及生命的心律失常。HERG编码心脏快速延迟整流钾通道，该通道介导心室动作电位的复极化。在本研究中，我们使用卵母细胞表达系统和电压钳技术来确定位于HERG氨基末端区域的八个长QT综合征相关突变（F29L、N33T、G53R、R56Q、C66G、H70R、A78P和L86R）的功能后果。当在卵母细胞中单独表达时，突变亚基形成了具有改变门控特性的功能性通道。所有突变均加速了失活过程。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会减少心脏动作电位复极化阶段的外向电流，并导致校正QT间期（QTc）延长。HERG的氨基末端区域最近已结晶，并显示具有一个Per-Arnt-Sim（PAS）结构域。这些突变的位置表明它们可能会破坏PAS结构域，并干扰其与HERG通道S4 - S5连接区的相互作用。
