In silico analysis of the dynamic regulation of cardiac electrophysiology by Kv11.1 ion-channel trafficking

Cardiac electrophysiology is regulated by continuous trafficking and internalization of ion channels occurring over minutes to hours. K(v)11.1 (also known as hERG) underlies the rapidly activating delayed-rectifier K+ current (I-Kr), 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 K(v)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 K(v)11.1 membrane levels while also producing a significant channel block. However, clinically relevant concentrations did not affect trafficking. Similarly, severe hypokalaemia reduced K(v)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 I-Kr due to faster kinetics, while after 24 h, I-Kr was decreased due to reduced K(v)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.