title: 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.affiliation: Provincial Clinical Medicine College of Fujian Medical University, Fuzhou 350001, Fujian, PR China.
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Guang׳anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cardiology, General Hospital of People׳s Liberation Army, Beijing 100853, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiology, General Hospital of People׳s Liberation Army, Beijing 100853, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Cardiology, General Hospital of People׳s Liberation Army, Beijing 100853, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Provincial Clinical Medicine College of Fujian Medical University, Fuzhou 350001, Fujian, PR China.
authors.forename: Guojian
authors.initials: G
authors.lastname: Xiang
authors.affiliation: Provincial Clinical Medicine College of Fujian Medical University, Fuzhou 350001, Fujian, PR China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wei
authors.affiliation: Department of Cardiology, General Hospital of People׳s Liberation Army, Beijing 100853, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Guang׳anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, PR China. Electronic address: xingyanwei12345@163.com.
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Cardiology, General Hospital of People׳s Liberation Army, Beijing 100853, PR China. Electronic address: liyangbsh@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D019943:Amino Acid Substitution; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001600:Berberine Alkaloids / Q000494:pharmacology*; D053840:Brugada Syndrome / Q000235:genetics* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D017930:Genes, Reporter / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D018613:Microscopy, Confocal; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009465:Neuromuscular Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D021381:Protein Transport / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D061585:Voltage-Gated Sodium Channel Agonists / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D001600:Berberine Alkaloids; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009465:Neuromuscular Agents; D011994:Recombinant Proteins; C568320:SCN5A protein, human; D061585:Voltage-Gated Sodium Channel Agonists; D049452:Green Fluorescent Proteins; C109505:allocryptopine
keywords: Alpha-allocryptopine; Brugada syndrome; Sodium channel; Trafficking deficiency