In silico analysis of the dynamic regulation of cardiac electrophysiology by Kv 11.1 ion-channel trafficking.

Abstract

Cardiac electrophysiology is regulated by continuous trafficking and internalization of ion channels occurring over minutes to hours. Kv 11.1 (also known as hERG) underlies the rapidly activating delayed-rectifier K+ current (IKr ), which plays a major role in cardiac ventricular repolarization. Experimental characterization of the distinct temporal effects of genetic and acquired modulators on channel trafficking and gating is challenging. Computer models are instrumental in elucidating these effects, but no currently available model incorporates ion-channel trafficking. Here, we present a novel computational model that reproduces the experimentally observed production, forward trafficking, internalization, recycling and degradation of Kv 11.1 channels, as well as their modulation by temperature, pentamidine, dofetilide and extracellular K+ . The acute effects of these modulators on channel gating were also incorporated and integrated with the trafficking model in the O'Hara-Rudy human ventricular cardiomyocyte model. Supraphysiological dofetilide concentrations substantially increased Kv 11.1 membrane levels while also producing a significant channel block. However, clinically relevant concentrations did not affect trafficking. Similarly, severe hypokalaemia reduced Kv 11.1 membrane levels based on long-term culture data, but had limited effect based on short-term data. By contrast, clinically relevant elevations in temperature acutely increased IKr due to faster kinetics, while after 24h, IKr was decreased due to reduced Kv 11.1 membrane levels. The opposite was true for lower temperatures. Taken together, our model reveals a complex temporal regulation of cardiac electrophysiology by temperature, hypokalaemia, and dofetilide through competing effects on channel gating and trafficking, and provides a framework for future studies assessing the role of impaired trafficking in cardiac arrhythmias. KEY POINTS: Kv 11.1 channels underlying the rapidly activating delayed-rectifier K+ current are important for ventricular repolarization and are continuously shuttled from the cytoplasm to the plasma membrane and back over minutes to hours. Kv 11.1 gating and trafficking are modulated by temperature, drugs and extracellular K+ concentration but experimental characterization of their combined effects is challenging. Computer models may facilitate these analyses, but no currently available model incorporates ion-channel trafficking. We introduce a new two-state ion-channel trafficking model able to reproduce a wide range of experimental data, along with the effects of modulators of Kv 11.1 channel functioning and trafficking. The model reveals complex dynamic regulation of ventricular repolarization by temperature, extracellular K+ concentration and dofetilide through opposing acute (millisecond) effects on Kv 11.1 gating and long-term (hours) modulation of Kv 11.1 trafficking. This in silico trafficking framework provides a tool to investigate the roles of acute and long-term processes on arrhythmia promotion and maintenance.