MOLECULAR PHYSIOLOGY OF LONG QT SYNDROME & IDIOPATHIC VENTRICULAR FIBRILLATION

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The long-term goals of this project are to understand the molecular basis of channel dysfunction caused by mutations in ion channel genes that cause cardiac arrhythmia, and to explore potential therapies at the cellular and organ level based on these findings. Subproject 1 will explore the mechanism of action and normalization of cardiac repolarization by an activator of KvLGT1 and cardiac I/Ks channels. A novel benzodiazepine (R-L3) was recently discovered that increases the magnitude of I/Ks and shortens action potential duration. We will study the effects of this compound on KvLGT1 and minK channel subunits heterologously expressed in Xenopus oocytes. We will also determine if this compound can suppress early after depolarizations in rabbit myocytes and prevent torsades de pointes in isolated perfused hearts. Subproject 2 will investigate the biophysical properties of mutations in SCN5A that cause long QT syndrome and idiopathic ventricular fibrillation. Gating and ionic currents recorded from sodium channels heterologously expressed in cultured mammalian cells will be used to understand abnormal channel function of SCN5A mutations. Subproject 3 will characterize mutations in HERG and newly discovered genes that cause long QT syndrome that are identified in Project 1. These studies will utilize both the oocyte and cultured mammalian cell expression systems. We will initially concentrate on mutations in HERG that will provide insights into the structural basis of channel function.