Electrophysiological and trafficking defects of the SCN5A T353I mutation in Brugada syndrome are rescued by alpha-allocryptopine
Electrophysiological and trafficking defects of the SCN5A T353I mutation in Brugada syndrome are rescued by alpha-allocryptopine
复制标题
α-别隐品可挽救 Brugada 综合征中 SCN5A T353I 突变的电生理和运输缺陷
DOI：
10.1016/j.ejphar.2014.09.028
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发表时间：
2015-01-05
影响因子：
5
通讯作者：
Li, Yang
中科院分区：
文献类型：
--
作者：
Zhang, Jiancheng;Chen, Yu;Li, Yang
布鲁格达综合征（BrS）会导致心律失常，进而导致心源性猝死，它与影响钠通道的功能丧失突变有关。在这里，我们研究了中草药中的α-别隐托品（All）对SCN5A T353I突变的拯救作用，该突变结合了运输异常和Brugada综合征。 HEK293 细胞中表达的 SCN5A-T353I 显示出仅为 WT 59.6% 的小峰值电流 (1(peak)) 和可观察到的持续电流 (I-sus)。我们发现 All 通过增强 Nav1.5 的质膜 (PM) 表达来强烈增强 T353I 通道的 I 峰，并在与携带突变通道的 HEK293 细胞共孵育 24 小时后挽救缺陷的运输。 All通过延长封闭状态失活（CSI）过程和缩短T3531突变失活恢复也有利于增加T3531突变的I峰。有趣的是，T3531的I-sus被All显着抑制，从而减少了LQT综合征3（LQT3）的发生。我们提供的证据表明 All 可以挽救 SCN5A-T353I 的运输缺陷并恢复细胞电生理特征。 All 的这一特性可能会使患有 BrS 相关 Nav1.5 通道的患者受益，并可能具有其他潜在的治疗效果。 (C) 2014 Elsevier B.V. 保留所有权利。
Brugada syndrome (BrS), which causes arrhythmias that lead to sudden cardiac death, is linked to loss-of-function mutations that affect sodium channels. Here, we investigate the rescue effect of alpha-allocryptopine (All) from Chinese herbal medicine in a T353I mutation of SCN5A, which combines trafficking abnormalities with Brugada syndrome. SCN5A-T353I expressed in HEK293 cells showed a small peak current (1(peak)) of only 59.6% of WT and an observably sustained current (I-sus). We found that All strongly enhanced the I-peak of the T353I channel by enhancing the plasma membrane (PM) expression of Nav1.5 and rescued defective trafficking after co-incubation with HEK293 cells that carry mutation channel 24 h. It is also beneficial to increase the I-peak of the T3531 mutation by All by prolonging the closed-state inactivation (CSI) process and shortening the recovery from inactivation of the T3531 mutation. Interestingly, the I-sus of T3531 was significantly inhibited by All, which reduces the occurrence of LQT syndrome 3 (LQT3). We provide evidence that All can rescue the trafficking deficiencies and restore the cellular electrophysiological characteristics of SCN5A-T353I. This feature of All may benefit patients with the BrS-associated Nav1.5 channel and might have other potential therapeutic effects. (C) 2014 Elsevier B.V. All rights reserved.