SUBCELLULAR DISTRIBUTION OF CARDIAC K CHANNELS

描述(改编自申请者的描述)：电压门控钾 通道在调节心肌细胞兴奋中起着重要作用。一次高潮 在长QT综合征患者中观察到心律失常的发生率， 一种疾病，由编码电压门控钾和 心脏中的钠通道。申请者已经创建了很长时间的老鼠模型 QT综合征，其中钾通道Kv1.5的表达明显 减少了。这项建议的目的是研究监管的机制 电压门控钾通道多肽转运、靶向和 在心肌细胞膜上表达。申请者建议识别 并对对聚集和组装至关重要的蛋白质进行了表征 一些膜下结合钾通道的大分子复合体。这 知识将被用来创建嵌合型钾通道并研究它们的 转基因小鼠体内表达及亚细胞靶向研究 用腺病毒和腺相关病毒载体在体内表达基因。这个 外源性钾通道表达的影响将用 单电池的电压钳位分析。QT间期和QT间期记录 清醒小鼠自发性心律失常及其诱发因素分析 由程序性室性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.