Calcium-Dependent Regulation of Potassium Channels in Cardiac Electrophysiology: A Computational Study

Abstract

Calcium-dependent regulation of several potassium channels has recently been identified, but its relative importance for atrial and ventricular electrophysiology, and potentially arrhythmogenesis, is incompletely understood. Here, we employed computational modeling to study calcium-dependent regulation of potassium channels in cardiac electrophysiology. Calcium-dependent regulation of the basal inward-rectifier (IK1), slow delayed-rectifier (IKs), and small-conductance calcium-activated (ISK) potassium currents was incorporated into established atrial (Grandi-Bers) and ventricular (O’Hara-Rudy) cardiomyocyte models and compared to simulations without calcium-dependent regulation. Calcium-dependent activation of IK1 and ISK shortened atrial and ventricular action potential (AP) duration (APD), but their regulation by rate-dependent intracellular calcium loading only modestly affected APD rate dependence. The impact of calcium-dependent potassium current regulation was limited because 1) IKs has a minor impact on repolarization under basal conditions and 2) calcium-dependent activation of IK1, IKs and ISK is already almost saturated at slow rates. Accordingly, after incorporating a gain-of-function mutation that increased IKs, calcium-dependent IKs activation reduced APD without modulating APD rate dependence. Furthermore, simulated L-type calcium channel inhibition lowered intracellular calcium, decreasing calcium-dependent regulation of potassium currents and significantly prolonging APD. Finally, simulated diastolic sarcoplasmic reticulum calcium releases produced delayed afterdepolarizations in the ventricular model and triggered APs in the atrial model. Calcium-dependent augmentation of potassium currents did not affect the threshold for triggered atrial APs, but significantly reduced afterdepolarization amplitude in the ventricle due to a calcium-dependent increase in IK1. This effect was not visible in the atrial model due to the smaller IK1 and the higher sensitivity for triggered APs. Taken together, physiologic calcium-dependent potassium-channel regulation has a modest impact on basal atrial and ventricular electrophysiology, but may be further enhanced during conditions of abnormal repolarization or impaired calcium handling, and as such may play a role in cardiac arrhythmogenesis.