Key Role of the Membrane Trafficking of Nav1.5 Channel Protein in Antidepressant-Induced Brugada Syndrome.
Key Role of the Membrane Trafficking of Nav1.5 Channel Protein in Antidepressant-Induced Brugada Syndrome.
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Nav1.5 通道蛋白的膜运输在抗抑郁药诱导的 Brugada 综合征中的关键作用。
DOI：
10.3389/fphys.2018.01230
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发表时间：
2018
影响因子：
4
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Chen X;Zhu C;Zhou H;Zhang Y;Cai Z;Wu H;Ren X;Gao L;Zhang J;Li Y
抗抑郁治疗已被发现与Brugada综合征(BRS)的发展有关，其机制尚未明确。本研究旨在探讨阿米替林诱导BRS的分子基础。采用新生大鼠心室肌细胞模型，观察阿米替林长期给药对NAV1.5的影响。应用膜片钳、免疫印迹和激光共聚焦显微镜技术研究NaV1.5的电生理特性、表达和分布。免疫共沉淀法研究NaV1.5与其相互作用的蛋白，包括锚蛋白G和抗肌营养不良蛋白的相互作用。长期服用阿米替林后，INA峰值下降幅度(56.64%)大于急性阿米替林治疗后(28%)。经阿米替林急性或长期治疗后，NaV1.5的失活缓慢恢复。细胞膜上NaV1.5的表达在阿米替林长期作用下的下降幅度大于阿米替林的急性作用。在阿米替林长期治疗后，我们观察到细胞膜上的NaV1.5蛋白减少，并破坏了NaV1.5与Ankyrin-G或dystrophin的共定位。免疫共沉淀实验进一步证明，经阿米替林长期治疗后，NaV1.5与Ankyrin-G或dystrophin的结合严重减弱，提示NaV1.5与ankyrin-G或dystrophin的相互作用失败。我们的数据表明，阿米替林的长期效应是阿米替林诱发BRS的重要贡献。阿米替林诱导BRS的机制与NaV1.5转运有关，并可通过Ankyrin-G、dystrophin和NaV1.5相互作用的破坏来解释。
Anti-depressant treatment has been found to be associated with the development of Brugada syndrome (BrS) through poorly defined mechanisms. Herein, this study aimed to explore the molecular basis for amitriptyline-induced BrS. The effects of long-term treatments of amitriptyline on Nav1.5 were investigated using neonatal rat ventricular myocytes. The electrophysiological properties, expression and distribution of Nav1.5 were studied using the patch clamp, Western blot and confocal laser microscopy assays. Interactions between Nav1.5 and its interacting proteins, including ankyrin-G and dystrophin, were evaluated by co-immunoprecipitation. A larger decrease in the peak INa occurred after long-term treatments to amitriptyline (56.64%) than after acute exposure to amitriptyline (28%). Slow recovery from inactivation of Nav1.5 was observed after acute or long-term treatments to amitriptyline. The expression of Nav1.5 on the cell membrane showed a larger decrease by long-term treatments to amitriptyline than by acute exposure to amitriptyline. After long-term treatments to amitriptyline, we observed reduced Nav1.5 proteins on the cell membrane and the disrupted co-localization of Nav1.5 and ankyrin-G or dystrophin. Co-immunoprecipitation experiments further testified that the combination of Nav1.5 and ankyrin-G or dystrophin was severely weakened after long-term treatments to amitriptyline, implying the failed interaction between Nav1.5 and ankyrin-G or dystrophin. Our data suggest that the long-term effect of amitriptyline serves as an important contribution to BrS induced by amitriptyline. The mechanisms of BrS induced by amitriptyline were related to Nav1.5 trafficking and could be explained by the disrupted interaction of ankyrin-G, dystrophin and Nav1.5.
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DOI：
10.1073/pnas.0403711101
发表时间：
2004-12-14
影响因子：
11.1
作者：
Mohler, PJ;Rivolta, I;Bennett, V
通讯作者：
Bennett, V
影响因子：
6.1
作者：
Juang, Jyh-Ming Jimmy;Chen, Ching-Yu Julius;Hsiung, Chao Agnes
通讯作者：
Hsiung, Chao Agnes
影响因子：
3.3
作者：
Murakoshi, Nobuyuki;Aonuma, Kazutaka
通讯作者：
Aonuma, Kazutaka
影响因子：
20.1
作者：
Gavillet, Bruno;Rougier, Jean-Sebastien;Abriel, Hugues
通讯作者：
Abriel, Hugues
影响因子：
2.7
作者：
Minoura Y;Di Diego JM;Barajas-Martínez H;Zygmunt AC;Hu D;Sicouri S;Antzelevitch C
通讯作者：
Antzelevitch C