快速延迟整流钾电流(rapidly activating com ponent of delayed rectifier potassium current,IKr)在心肌动作电位复极化过程中发挥重要作用。HERG基因编码心脏快速延迟整流钾通道的α亚基,HERG基因突变导致遗传性长QT间期综合征(long ...快速延迟整流钾电流(rapidly activating com ponent of delayed rectifier potassium current,IKr)在心肌动作电位复极化过程中发挥重要作用。HERG基因编码心脏快速延迟整流钾通道的α亚基,HERG基因突变导致遗传性长QT间期综合征(long QT syndrome,LQTS),另外IKr/HERG通道是绝大多数能引起心脏QT间期延长药物的作用靶标,其他一些化学结构不同的药物也可阻断该通道,引起QT间期延长,甚至发展成获得性心律失常。本文从门控机制及功能、HERG通道相关的心律失常、药物与通道相互作用机制、优化通道靶点的策略等四个方面综述IKr/HERG通道在抗心律失常方面的最新研究进展。展开更多
Objective:The long QT syndrome type 2 is caused by the loss-of-function mutations in the KCNH2 gene,which encodes hERG1,the voltage-gated potassium channel.The hERG1 channels conduct rapid delayed rectifier K^(+)curre...Objective:The long QT syndrome type 2 is caused by the loss-of-function mutations in the KCNH2 gene,which encodes hERG1,the voltage-gated potassium channel.The hERG1 channels conduct rapid delayed rectifier K^(+)currents(I_(Kr))in the human cardiac tissue.KCNH2 encodes 2 main isoforms-hERG1a and hERG1b,which assemble to form the homomeric or heteromeric hERG1 channels.However,the functional characteristics of the heteromeric hERG1 channels in long QT syndrome type 2 are not clear.In this study,a novel mutation in the N-terminus of hERG1a(F129l)was identified in a proband of long QT syndrome type 2.The purpose of this study was to identify the electrophysiological change of homomeric and heteromeric hERG1 channels with theF129l-hERG1a.Methods:Candidate genes were screened by direct sequencing.F129l-hERG1a was cloned in the pcDNA3.1 vector by site-directed mutagenesis.Then,the wild-type(WT)hERG1a and/or F129l-hERG1a were transiently expressed in the HEK293 cells with or without hERG1b co-expression.The expression levels of the transgenes,cellular distribution of hERG1a and hERG1b,and the electrophysiological features of the homomeric and the heteromeric hERG1 channels with the WT-hERG1a or F129l-hERG1a were analyzed using whole-cell patch-clamp electrophysiology,western blotting,and immunofluorescence techniques.Results:The proband was clinically diagnosed with long QT syndrome type 2 and carried a heterozygous mutation c.385T>A(F1291)in the KCNH2 gene.Electrophysiology study proved that the F129l substitution in hERG1a significantly decreased I_(Kr) in both the homomeric and heteromeric hERG1channels by 86%and 70%,respectively(WT-hERG1a(54.88±18.74)pA/pF vs.F129l-hERG1a(7.34±1.90)pA/pF,P<0.001;WT-hERG1a/hERG1b(89.92±24.51)pA/pF vs.F129l-hERG1a/hERG1b(26.54±9.83)pA/pF,P<0.001).The voltage dependence of I_(Kr) activation(V_(1/2) and k)was not affected by the mutation in both the homomeric and heteromeric hERG1 channels.The peak current densities and the kinetic characteristics of I_(Kr) were comparable for both 展开更多
文摘Objective:The long QT syndrome type 2 is caused by the loss-of-function mutations in the KCNH2 gene,which encodes hERG1,the voltage-gated potassium channel.The hERG1 channels conduct rapid delayed rectifier K^(+)currents(I_(Kr))in the human cardiac tissue.KCNH2 encodes 2 main isoforms-hERG1a and hERG1b,which assemble to form the homomeric or heteromeric hERG1 channels.However,the functional characteristics of the heteromeric hERG1 channels in long QT syndrome type 2 are not clear.In this study,a novel mutation in the N-terminus of hERG1a(F129l)was identified in a proband of long QT syndrome type 2.The purpose of this study was to identify the electrophysiological change of homomeric and heteromeric hERG1 channels with theF129l-hERG1a.Methods:Candidate genes were screened by direct sequencing.F129l-hERG1a was cloned in the pcDNA3.1 vector by site-directed mutagenesis.Then,the wild-type(WT)hERG1a and/or F129l-hERG1a were transiently expressed in the HEK293 cells with or without hERG1b co-expression.The expression levels of the transgenes,cellular distribution of hERG1a and hERG1b,and the electrophysiological features of the homomeric and the heteromeric hERG1 channels with the WT-hERG1a or F129l-hERG1a were analyzed using whole-cell patch-clamp electrophysiology,western blotting,and immunofluorescence techniques.Results:The proband was clinically diagnosed with long QT syndrome type 2 and carried a heterozygous mutation c.385T>A(F1291)in the KCNH2 gene.Electrophysiology study proved that the F129l substitution in hERG1a significantly decreased I_(Kr) in both the homomeric and heteromeric hERG1channels by 86%and 70%,respectively(WT-hERG1a(54.88±18.74)pA/pF vs.F129l-hERG1a(7.34±1.90)pA/pF,P<0.001;WT-hERG1a/hERG1b(89.92±24.51)pA/pF vs.F129l-hERG1a/hERG1b(26.54±9.83)pA/pF,P<0.001).The voltage dependence of I_(Kr) activation(V_(1/2) and k)was not affected by the mutation in both the homomeric and heteromeric hERG1 channels.The peak current densities and the kinetic characteristics of I_(Kr) were comparable for both
