Contribution of the Slow Delayed Rectifier K+ current to Pacemaker Activity of the Human Sinoatrial Node

Arie Verkerk and Ronald Wilders
Academic Medical Center, University of Amsterdam


Abstract

The slow delayed rectifier K+ current (IKs) is present in sinoatrial node (SAN) cells of various species, but both in vitro and in silico data on the contribution of IKs to SAN pacemaker activity are not consistent. To assess the contribution of IKs to human SAN pacemaker activity, we experimentally determined the biophysical properties of IKs, both under control conditions and upon β-adrenergic stimulation, and used the thus obtained data in computer simulations of human SAN pacemaker activity. KCNQ1/KCNE1 channels were expressed in HEK-293 cells through transfection with both KCNQ1 and KCNE1 cDNA, encoding the α and β subunits of the IKs channel, respectively. KCNQ1/KCNE1 current was recorded at 37°C in absence and presence of forskolin (10 µM) to increase the cAMP level, thus mimicking β-adrenergic stimulation. Human SAN pacemaker activity was simulated using the Fabbri–Severi model of a single human SAN cell, with the biophysical properties of IKs based on our experimental observations. Block of IKs under control conditions resulted in a 15.4% increase in pacing rate of the model cell, demonstrating that the inhibiting effect of IKs on diastolic depolarization dominated over its shortening effect on action potential duration. Running the model with its ‘1 µM isoprenaline' settings, thus simulating β-adrenergic stimulation, revealed higher effects of IKs block, the increase in pacing rate now amounting to 29.4%. These higher effects were not only due to the 25% increase in IKs conductance, the −14.6 mV shift in its steady-state activation curve, and the ≈40% increase in its activation rate upon β-adrenergic stimulation, but also to the shorter diastolic interval between subsequent action potentials available for IKs deactivation during the higher pacing rate induced by the β-adrenergic stimulation. We conclude that IKs exerts an important slowing effect on human SAN pacemaker activity, in particular during β-adrenergic stimulation.