Pathogenic mutations perturb calmodulin regulation of Nav1.8 channel
Pathogenic mutations perturb calmodulin regulation of Nav1.8 channel
复制标题
DOI：
10.1016/j.bbrc.2020.08.010
复制
发表时间：
2020-11-26
影响因子：
3.1
通讯作者：
Darbar, Dawood
中科院分区：
文献类型：
--
作者：
Hong, Liang;Zhang, Meihong;Darbar, Dawood
电压门控钠通道在心脏动作电位的产生和传播中起关键作用。新出现的数据表明，由SCN 10A基因编码的Na（v）1.8通道是心脏传导的调节剂，并且该基因的变异与心律失常如心房颤动（AF）和Brugada综合征（BrS）相关。电压门控钠通道含有钙调素（CaM）结合的IQ结构域，参与通道的慢失活，我们研究了CaM对Na（v）1.8通道功能的调节作用，发现CaM增强Na（v）1.8通道的慢失活和钠电流的超极化稳态失活曲线。CaM对通道门控的影响在Na（v）1.8通道截断IQ域中被破坏。我们研究了与AF和BrS相关的Na（v）1.8 IQ结构域突变，发现BrS连锁突变（R1863Q）减少了CaM诱导的超极化位移，AF连锁突变（R1869C和R1869G）破坏了CaM诱导的增强失活，并且在所有致病突变中，CaM对缓慢失活的发育和恢复的影响都减弱了。我们的研究结果表明，钙调素的作用，在调节Na（v）1.8通道功能的心律失常。爱思唯尔公司出版
The voltage-gated sodium channels play a key role in the generation and propagation of the cardiac action potential. Emerging data indicate that the Na(v)1.8 channel, encoded by the SCN10A gene, is a modulator of cardiac conduction and variation in the gene has been associated with arrhythmias such as atrial fibrillation (AF) and Brugada syndrome (BrS). The voltage gated sodium channels contain a calmodulin (CaM)-binding IQ domain involved in channel slow inactivation, we here investigated the role of CaM regulation of Na(v)1.8 channel function, and showed that CaM enhanced slow inactivation of the Na(v)1.8 channel and hyperpolarized steady-state inactivation curve of sodium currents. The effects of CaM on the channel gating were disrupted in the Na(v)1.8 channel truncated IQ domain. We studied Na(v)1.8 IQ domain mutations associated with AF and BrS, and found that a BrS-linked mutation (R1863Q) reduced the CaM-induced hyperpolarization shift, AF-linked mutations (R1869C and R1869G) disrupted CaM-induced enhanced inactivation, and effects of CaM on both development and recovery from slow inactivation were attenuated in all pathogenic mutations. Our findings indicate a role of CaM in the regulation of Na(v)1.8 channel function in cardiac arrhythmias. Published by Elsevier Inc.