SUBCELLULAR DISTRIBUTION OF CARDIAC K CHANNELS

Brigham And Women'S Hospital, Boston MA

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Abstract

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.