Targeting Potassium Channel Trafficking in Cardiac Arrhythmia

Abstract

Ion channel trafficking, this is the transport of ion channel proteins within the heart cell, is an underestimated cause of severe cardiac arrhythmias. Importantly, it is often missed in initial cardiac safety assessment during the drug development process. The main focus of this thesis is exploring the role of cardiac potassium channel trafficking in arrhythmia and new means to counteract the latter. The inward rectifier KIR2.x and delayed rectifier Kv11.1 (hERG) channels were emphasized. In Chapter 2, we listed several inherited diseases that relate to altered ion channel function and linked it to channel mistrafficking and recognized mutation clusters. In Chapter 3, we also reviewed current animal models applied in cardiac arrhythmia studies to find appropriate models to enable the transition of ion-channel trafficking studies from in vitro to in vivo systems. The role of ion channel trafficking from several aspects, for example, pharmacological activation and structure identification, was evaluated in Chapter 4 - 6. In Chapter 7, we further identified the functional properties of several Pentamidine analogues, a typical Kv11.1 trafficking inhibitor. Finally, in Chapter 8, we summarized and discussed the results and conclusions from previous chapters. To conclude, potassium channel trafficking is a valid and important target for treating cardiac arrhythmia, using a pharmacological approach.