PTC124不影响心脏SCN5A通道和HERG通道的电生理特性  

The Chemical Compound PTC124 Does Not Affect Cellular Electrophysiology of Cardiac SCN5A and HERG Channels

作　　者：滕思勇[1] 黄健[1] 郝杰[1] 杜忠鹏[1] 浦介麟[1] 惠汝太 

机构地区：[1]国家心血管病中心 阜外心血管病医院

出　　处：《中国分子心脏病学杂志》2013年第3期565-568,共4页Molecular Cardiology of China

基　　金：国家自然科学基金(30971176)

摘　　要：目的无义突变产生提早出现的终止密码子(Premature termination codon,PTC),其主要致病机制是突变基因单倍体表达不足,见于心脏SCN5A和HERG基因。SCN5A无义突变导致心脏传导功能障碍、扩张性心肌病和Brugada综合征(BrS)等疾病,HERG无义突变导致长QT综合征、扩张性心肌病等疾病,目前尚无有效方法根治这类疾病,但药物将是治疗这类突变相关性疾病的最佳选择。近年来开发的口服药物PTC124,能够选择地抑制过早出现的终止密码子,诱导核糖体通读、不影响正常的终止密码子。为了评价该药物的安全性,本研究检测了PTC124对心脏钠通道和HERG通道的电生理特性。方法构建心脏SCN5A和HERG基因的真核表达载体,分别转染HEK293细胞,应用PTC124处理细胞72小时,全细胞膜片钳记录钠通道和HERG通道的表达电流和动力学,蛋白印迹证明钠通道和HERG通道的表达水平。结果 PTC124处理或未处理的钠电流密度分别-240.2±24.8pA/pF和-238.5±25.2pA/pF,PTC124处理或未处理的HERG激活电流密度分别为43.2±4.3pA/pF和41.9±5.0pA/pF,PTC124处理或未处理的HERG失活电流密度分别为69.9±3.8pA/pF和70.1±3.7pA/pF,激活或失活动力学参数均没有统计学差异。结论 PTC124不影响心脏钠通道和HERG通道的电生理特性。该研究为今后评估这种疗法的使用价值,治疗具有潜在的致命性心律失常性疾病患者的安全性提供依据。Purpose Nonsense mutations that create premature termination codons （PTC） leading to disease by a mechanism of haploinsufficiency are relatively common in the SCN5A or HERG gene encoding the major sodium channel and potassium in heart. PTCs in SCN5A are associated with isolated conduction disease and Brugada syndrome （BrS）; PTCs in HERG are associated with isolated conduction disease and long QT syndrome （LQTS）. Pharmacological therapy does not exist for these disorders, but would be highly beneficial. Recently, an orally bio-available drug capable of suppressing premature termination, PTC 124, has been identified that selectively induces ribosomal read-through of premature but not normal termination codons. In this study, we tested the acute and long-term effects of PTC124 on SCN5A or HER（]. Methods Constructing cardiac SCN5A and HERG gene eukaryotic expression vector, transfecting HEK293 cells, PTC 124 exposure of transfected cells for 72 hours, whole-cell patch clamp recording currents and dynamics of sodium channels and HERG channels. Results sodium current density with or without PTCI24 were -240.2±24.8pA/pF and -238.5±25.2pA/pF, HERG activation current density with or without PTCI24 were 43.2±4.3pA/pF and 41.9±5.0pA/pF, HERG inactivation current density with or without PTC 124 were 69.9±3.8pA/pF and 70. 1±3.7pA/pF, activation or deactivation or inactivation kinetics were not statistically significant. Conclusion PTC124 does not affect the electrophysiological properties of cardiac sodium channels and HERG channel. These experiments form the basis for future studies evaluating the use of this therapy in preventing potentially lethal arrhythmias in patients with BrS and/or conduction disease.

关 键 词：PTC124 心律失常 SCN5A HERG 电生理特性 

分 类 号：R541.7[医药卫生—心血管疾病]