A novel mechanism associated with idiopathic ventricular fibrillation (IVF) mutations R1232W and T1620M in human cardiac sodium channels.
A novel mechanism associated with idiopathic ventricular fibrillation (IVF) mutations R1232W and T1620M in human cardiac sodium channels.
复制标题
与人心脏钠通道中特发性心室颤动 (IVF) 突变 R1232W 和 T1620M 相关的新机制。
DOI：
10.1007/s004240100529
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Ruben,PC
中科院分区：
文献类型：
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作者：
Vilin,YY;Fujimoto,E;Ruben,PC
与特发性心室颤动（IVF）相关的两个突变位于人心脏钠通道（hNaV1.5）α亚基的片段DIIIS 1-S2（R1232 W）和DIVS 3-S4（T1620 M）之间的细胞外环内。我们用细胞贴附宏斑技术研究了野生型hNaV1.5通道和R1232 W/T1620 M双突变hNaV1.5通道在异种卵母细胞中的表达。我们证明，这些突变不稳定的快速失活状态（描述与两个状态的一级反应模型），通过降低反应价，加速恢复，并减缓发病的快速失活，共同导致延迟衰减的宏观电流。hNaV1.5通道中的R1232 W/T1620 M突变也显著增加稳态通道可用性，表明突变的通道占据慢失活状态少于hNaV1.5通道。在重复去极化脉冲的压力下，与野生型通道相比，R1232 W/T1620 M通道表现出较少的使用依赖性电流降低。我们认为，增加通道的可用性加上不稳定的快速失活有助于R1232 W/T1620 M突变的病理效应，并导致体内心脏组织的兴奋性增加。
Two mutations associated with idiopathic ventricular fibrillation (IVF) are localized within extracellular loops between segments DIIIS1-S2 (R1232W) and DIVS3-S4 (T1620M) of the human cardiac sodium channel (hNaV1.5) α-subunit. We studied wild-type hNaV1.5 channels and hNaV1.5 channels with the R1232W/T1620M double mutation expressed inXenopusoocytes using the cell-attached macropatch technique. We demonstrate that these mutations destabilize the fast-inactivated state (described with a two-state first-order reaction model) by decreasing reaction valence, accelerating recovery, and slowing the onset of fast inactivation, collectively resulting in delayed decay of macroscopic currents. R1232W/T1620M mutations in hNaV1.5 channels also significantly increase steady-state channel availability, indicating that mutated channels occupy the slow inactivated state less than hNaV1.5 channels. Under the stress of repetitive depolarizing pulses, R1232W/T1620M channels demonstrate less use-dependent current reduction compared to wild-type channels. We propose that increased channel availability coupled with destabilized fast inactivation contributes to the pathological effect of R1232W/T1620M mutations, and leads to increased excitability of cardiac tissue in vivo.