SUBCELLULAR DISTRIBUTION OF CARDIAC K CHANNELS

描述（改编自申请人的描述）：电压门控钾 通道在调节心脏细胞兴奋中起重要作用。高 在长QT综合征患者中观察到心律失常的发生率， 由编码电压门控钾的基因突变引起的疾病， 心脏中的钠通道申请人长期以来一直在建立小鼠模型， QT综合征，其中钾通道Kv1.5的表达显著增加， 降低这项建议的目的是研究调节机制， 电压门控钾通道多肽运输、靶向和 在心肌细胞膜中表达。申请人建议确定 并描述了蛋白质的特征，这些蛋白质对聚集和组装很重要， 一些膜下的大分子复合物结合钾通道。这 知识将被用于创建嵌合钾通道，并研究其 使用转基因小鼠进行体内表达和亚细胞靶向以及 使用腺病毒和腺相关病毒载体的体内基因表达。的 外源性钾通道表达的影响将使用 单细胞的电压钳分析。记录QT间期和 清醒小鼠自发性心律失常及诱发因素分析 程序性心室刺激引起的心律失常。

DESCRIPTION (adapted from the applicant's description): Voltage-gated potassium channels play an important role in regulating cardiac cell excitation. A high incidence of cardiac arrhythmia is observed in patients with long QT syndrome, a disease caused by mutations in genes that encode voltage-gated potassium and sodium channels in the heart. The applicant has created a mouse model for long QT syndrome in which the expression of a potassium channel, Kv1.5, is markedly reduced. The purpose of this proposal is to study the mechanisms that regulate voltage-gated potassium channel polypeptide trafficking, targeting and expression in the membrane of cardiac cells. The applicant proposes to identify and characterize the proteins that are important for clustering and assembly of some submembranous macromolecular complexes that bind potassium channels. This knowledge will be used to create chimeric potassium channels and study their expression and subcellular targeting in vivo using transgenic mice as well as in vivo gene expression using adeno- and adeno-associated viral vectors. The effect of expression of exogenous potassium channels will be studied using voltage-clamp analysis of single cells. Recording of QT interval and spontaneous arrhythmias in conscious mice, and analysis of inducible arrhythmias by programmed ventricular stimulation.