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

Cardiac electrophysiology is regulated by continuous trafficking and internalisation 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 to elucidate these effects, but no currently available model incorporates ion-channel trafficking. Here, we present a novel computational model reproducing the experimentally observed production, forward trafficking, internalisation, 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 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 hours, 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. KEY POINTS: Kv11.1 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. Kv11.1 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 Kv11.1 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 Kv11.1 gating and long-term (hours) modulation of Kv11.1 trafficking. This in-silico trafficking framework provides a tool to investigate the roles of acute and long-term processes on arrhythmia promotion and maintenance. Abstract figure legend K v 11.1 channels underly the rapidly-activating delayed-rectifier K + current and are crucial for cardiac ventricular repolarization. K v 11.1 channels are continuously trafficking to and from the plasma membrane, a process which is temperature- and potassium-dependent and modulated by various drugs. Here, we developed a novel computer model of K v 11.1 trafficking that reproduces a wide range of experimental data, including the acute and long-term effects of temperature, extracellular K + concentration, and drugs. The model reveals complex dynamic regulation of cardiac repolarization through opposing short- and long-term effects of these factors on K v 11.1 channel gating and trafficking, indicating that assessment of their acute effects is insufficient to determine potential proarrhythmic effects. The black dotted arrows represent stimulating effects, while the red solid lines represent inhibitory effects. The Golgi complex, drugs, and thermometer were created with BioRender.com. This article is protected by copyright. All rights reserved.