Electrophysiological and trafficking defects of the SCN5A T353I mutation in Brugada syndrome are rescued by alpha-allocryptopine.

Abstract

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 (I(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 T353I mutation by All by prolonging the closed-state inactivation (CSI) process and shortening the recovery from inactivation of the T353I mutation. Interestingly, the I(sus) of T353I 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.

• Authors: Jiancheng Zhang, Yu Chen, Jie Yang, Bin Xu, Yi Wen, Guojian Xiang, Guoliang Wei, Chao Zhu, Yanwei Xing, Yang Li
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 746 Pg. 333-43 (Jan 05 2015) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 25261036 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Arrhythmia Agents
• Berberine Alkaloids
• NAV1.5 Voltage-Gated Sodium Channel
• Neuromuscular Agents
• Recombinant Proteins
• SCN5A protein, human
• Voltage-Gated Sodium Channel Agonists
• Green Fluorescent Proteins
• allocryptopine

Topics

• Amino Acid Substitution
• Anti-Arrhythmia Agents (pharmacology)
• Berberine Alkaloids (pharmacology)
• Brugada Syndrome (genetics, metabolism)
• Cell Membrane (drug effects, metabolism)
• Genes, Reporter (drug effects)
• Green Fluorescent Proteins (genetics, metabolism)
• HEK293 Cells
• Humans
• Kinetics
• Membrane Potentials (drug effects)
• Microscopy, Confocal
• Mutagenesis, Site-Directed
• Mutation
• NAV1.5 Voltage-Gated Sodium Channel (chemistry, genetics, metabolism)
• Neuromuscular Agents (pharmacology)
• Patch-Clamp Techniques
• Protein Transport (drug effects)
• Recombinant Proteins (chemistry, metabolism)
• Voltage-Gated Sodium Channel Agonists (pharmacology)