A novel SCN5A mutation associated with long QT-3: altered inactivation kinetics and channel dysfunction.
A novel SCN5A mutation associated with long QT-3: altered inactivation kinetics and channel dysfunction.
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DOI：
10.1152/physiolgenomics.00039.2002
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发表时间：
2002-09
影响因子：
4.6
通讯作者：
I. Rivolta;C. Clancy;M. Tateyama;Huajun Liu;S. Priori;R. Kass
中科院分区：
文献类型：
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作者：
I. Rivolta;C. Clancy;M. Tateyama;Huajun Liu;S. Priori;R. Kass
编码心脏钠离子通道α亚基的基因（SCN5A）突变可导致先天性长QT综合征（LQT-3）。在这里，我们描述了一种新的LQT-3突变I1768V (I1768V)，位于结构域IV的第六个跨膜跨越段。这种突变的不寻常之处在于它位于跨膜跨越区域内，并且不会促进通常观察到的与通道功能增益（破裂）相对应的持续内向电流。相反，I1768V增加了从失活中恢复的速率，增加了通道的可用性，观察到稳态失活曲线的正偏移（+7.6 mV）。使用心脏Na+通道的马尔可夫模型，我们模拟了门控行为的这些变化，并证明了从失活恢复速率的微小增加足以解释所有实验观察到的电流变化。通道门控的这些改变导致窗口电流的增加，这可能会破坏心脏再极化。
Mutations in the gene (SCN5A) encoding the alpha-subunit of the cardiac Na+ channel cause congenital long QT syndrome (LQT-3). Here we describe a novel LQT-3 mutation I1768V (I1768V) located in the sixth transmembrane spanning segment of domain IV. This mutation is unusual in that it is located within a transmembrane spanning domain and does not promote the typically observed sustained inward current corresponding to a gain of channel function (bursting). Rather, I1768V increases the rate of recovery from inactivation and increases the channel availability, observed as a positive shift of the steady-state inactivation curve (+7.6 mV). Using a Markovian model of the cardiac Na+ channel, we simulated these changes in gating behavior and demonstrated that a small increase in the rate of recovery from inactivation is sufficient to explain all of the experimentally observed current changes. The effect of these alterations in channel gating results in an increase in window current that may act to disrupt cardiac repolarization.