Small molecule targeting of cardiac hERG channels to protect against arrhythmias'

The hERG potassium channel encoded by the ether-a-go-go-related gene (hERG) is essential for ventricular repolarization. These channels have a distinctive kinetic profile in that they conduct a modest current during the plateau phase, attain their maximum conductance during phase 3 of cardiac repolarization, and then close slowly. Due to acquired or hereditary conditions, dysfunction of these channels reduces hERG currents, prolongs action potential length (as shown by a prolonged QT interval), and predisposes individuals to potentially fatal ventricular arrhythmias. This-relationship between hERG dysfunction and QT prolongation (Long QT Syndrome, LQTS) has sparked interest in the role of hERG channels in phase 3 repolarization and arrhythmia generation and the possibility that small molecules hERG agonists may be utilized to restore function. A series of small molecules have been found and classified according to their mode of action. In -vitro and in -vivo investigations have shown that Type 2 activators that enhance hERG currents by decreasing channel inactivation, risk over-correction of the action potential and Short QT Syndrome. Type 1 activators, which preferentially slow the deactivation of hERG channels, on the other hand, may provide a more subtle restoration of hERG currents. A few studies have postulated that the slow deactivation of hERG channels may suppress triggered activity by allowing protective repolarizing current flow in response to premature depolarizations arriving in the refractory period. However, there are no direct experimental correlations between these protective hERG currents and ventricular arrhythmia, or the effects of manipulation of deactivation by Type 1 hERG activators. In my thesis, I examine the role of hERG protective currents and the use of a hERG Type 1 activator as a mechanism based therapy for both acquired and inherited forms of LQTS. Using a translational approach ranging in complexity from single cells to the entire organ these studies aim to provide improved understanding of the pathogenic mechanisms associated with hERG channel dysfunction and the effect of targeted slowing of hERG deactivation in suppressing arrhythmias.