In Silico Model of SK Channel Gating, Temperature Dependence, and Calcium Sensitivity

Ilse van Herck1, Bo H. Bentzen2, Vincent Seutin3, Jussi T. Koivumäki4, Mary M. Maleckar5, Neil V. Marrion6, Andrew G. Edwards1
1Simula Research Laboratory, 2Acesion Pharma, 3Neurophysiology unit, GIGA Neurosciences, University of Liège, 4BioMediTech Institute and Faculty of Biomedical Sciences and Engineering, Tampere University of Technology, 5Modeling, Allen Institute for Cell Science, 6School of Physiology, Pharmacology and Neuroscience, University of Bristol


Abstract

The small conductance calcium activated potassium (SK) channel contributes to repolarization of the atrial action potential and is thought to be involved in the onset and progression of atrial fibrillation (AF). In vitro, in vivo and genome-wide association studies have shown functional and genetic links between variations of SK current and AF initiation and progression. In large animal models, SK inhibition has been shown to terminate and protect against AF. Regardless, the effect of SK inhibition or enhancement on human atrial electrophysiology is limited and controversial.

In silico modeling provides a potential framework for integrating data collected in cell and animal models with the known characteristics of human physiology, disease mechanisms, and treatment options. However, current atrial myocyte models do not include biophysical SK channel formulations. Here we provide a new and detailed SK model built from single-channel and excised inside-out macropatch recordings.

Single channel patch clamp data corroborated the previously reported structure with gating kinetics from the neuronal SK2 channel: 4 closed and 2 open states. Furthermore, inside-out macropatch data showed a strong effect of temperature on calcium sensitivity of the SK channel. At room temperature the EC50 for hSK2 and hSK3 was 0.38 ± 0.02 µM and 0.53 ± 0.07 µM respectively. Increasing the temperature to 37°C caused a leftward shift towards the diastolic range for both hSK2 and hSK3 (EC50 = 0.28 ± 0.01 µM and 0.23 ± 0.02 µM, respectively). These novel in vitro data for SK calcium sensitivity and temperature dependence were incorporated into a Markov model of SK gating dynamics. As expected this biophysically detailed SK channel model shortened the AP when incorporated to an atrial cell model.

This novel computational model of SK current and gating enables further in silico assessment of SK channel dynamics in atrial electrophysiology and involvement in atrial arrhythmogenesis.