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

The slow delayed rectifier K+ current (IKs) is present in sinoatrial node (SAN) cells of various species, but data on the contribution of IKs to SAN pacemaker activity are not consistent. Yet, sinus bradycardia is a common finding in case of gain-of-function mutations in the KCNQ1 gene, encoding the pore-forming α -subunit of the IKs channel. We carried out computer simulations of human SAN pacemaker activity using the Fabbri-Severi model of a single human SAN cell. Biophysical properties of IKs were updated, based on our recent patch clamp data on IKs channels expressed in HEK-293 cells. Under vagal tone, block of the original IKs of the Fabbri-Severi model had only a marginally small effect on action potential duration and diastolic depolarization, and thus cycle length. However, with the formulation of IKs based on our patch clamp data, block of IKs had a substantial effect on diastolic depolarization and cycle length, increasing pacing rate by 17%. A qualitatively similar, but less substantial effect was observed under control conditions and under \beta -adrenergic tone, with an increase in pacing rate of 5.2% in either case. Simulation of a gain-of-function mutation in KCNQ1 revealed a strong bradycardic effect during vagal tone. We conclude that IKs contributes to human SAN pacemaker activity at all levels of autonomic tone.