AUTHOR=Chen Xi , Zhu Chao , Zhou Hao , Zhang Yu , Cai Zhongqi , Wu Honglin , Ren Xiaomeng , Gao Lei , Zhang Jiancheng , Li Yang 

TITLE=Key Role of the Membrane Trafficking of Nav1.5 Channel Protein in Antidepressant-Induced Brugada Syndrome

JOURNAL=Frontiers in Physiology

VOLUME=Volume 9 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2018.01230

DOI=10.3389/fphys.2018.01230

ISSN=1664-042X

ABSTRACT=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 chronic blockade effects 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 dystrophic, were evaluated by co-immunoprecipitation. 
A larger decrease in the peak INa occurred after chronic exposure to amitriptyline (56.64%) than after acute exposure to amitriptyline (28%). Slow recovery from  inactivation of Nav1.5 was observed after acute or chronic exposure to amitriptyline. The expression of Nav1.5 on the cell membrane showed a larger decrease by chronic exposure to amitriptyline than by acute exposure to amitriptyline. After chronic exposure to amitriptyline, we observed retention of Nav1.5 proteins in the endoplasmic reticulum 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 chronic exposure to amitriptyline, implying the failed interaction between Nav1.5 and ankyrin-G or dystrophin. 
Our data suggest that the chronic effect 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.