Smits Jeroen P P, Veldkamp Marieke W, Bezzina Connie R, Bhuiyan Zahir A, Wedekind Horst, Schulze-Bahr Eric, Wilde Arthur A M
Experimental and Molecular Cardiology Group, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Cardiovasc Res. 2005 Aug 15;67(3):459-66. doi: 10.1016/j.cardiores.2005.01.017.
Congenital long QT syndrome type 3 (LQT3) is an inherited cardiac arrhythmia disorder due to mutations in the cardiac sodium channel gene, SCN5A. Although most LQT3 mutations cause a persistent sodium current, increasing diversity in the disease mechanism is shown. Here we present the electrophysiological properties of the A1330T sodium channel mutation (DIIIS4-S5 linker). Like the A1330P, LQT3 mutation, A1330T, causes LQT3 in the absence of a persistent current.
A1330T, A1330P and wild-type sodium channels were expressed in HEK-293 cells and characterized using the whole-cell configuration of the patch-clamp technique.
The A1330T mutation shifts positively the voltage-dependence of inactivation and speeds recovery from inactivation. Measurements of sodium window (I(Na, window)) currents revealed a positive shift of the I(Na, window) voltage range for both 1330 mutants, with in addition an increase in I(Na, window) magnitude for the A1330P mutant. Action potential (AP) clamp experiments revealed that these changes in I(Na, window) properties cause an increased inward current during the initial part of phase 4 repolarization of the AP.
Our findings indicate that the alanine at position 1330 in the DIIIS4-S5 linker of the cardiac sodium channel has a role in channel fast inactivation. Substitution by a threonine shifts the voltage range of I(Na, window) activity to more positive potentials. Here the counter-acting effect of outward K+ current is reduced and may delay AP repolarization, explaining the LQT3 phenotype.
先天性3型长QT综合征（LQT3）是一种遗传性心律失常疾病，由心脏钠通道基因SCN5A突变引起。尽管大多数LQT3突变会导致持续性钠电流，但疾病机制的多样性正在增加。本文介绍了A1330T钠通道突变（DIIIS4-S5连接区）的电生理特性。与A1330P这种LQT3突变一样，A1330T在没有持续性电流的情况下也会导致LQT3。
将A1330T、A1330P和野生型钠通道在HEK-293细胞中表达，并使用膜片钳技术的全细胞模式进行表征。
A1330T突变使失活的电压依赖性正向偏移，并加快失活后的恢复。钠窗电流（I(Na, window)）测量显示，两个1330突变体的I(Na, window)电压范围均正向偏移，此外，A1330P突变体的I(Na, window)幅度增加。动作电位（AP）钳实验表明，I(Na, window)特性的这些变化会导致AP复极化第4相初始部分的内向电流增加。
我们的研究结果表明，心脏钠通道DIIIS4-S5连接区1330位的丙氨酸在通道快速失活中起作用。苏氨酸取代使I(Na, window)活性的电压范围向更正电位偏移。此处外向K+电流的抵消作用减弱，可能会延迟AP复极化，从而解释了LQT3表型。
