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

The slow delayed rectifier $K^{+}$ current $(I_{Ks})$ is present in sinoatrial node $(SAN)$ cells of various species, but data on the contribution of $I_{Ks}$ 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 $\alpha$ -subunit of the $I_{Ks}$ 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 $I_{Ks}$ were updated, based on our recent patch clamp data on $I_{Ks}$ channels expressed in HEK-293 cells. Under vagal tone, block of the original $I_{Ks}$ 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 $I_{Ks}$ based on our patch clamp data, block of $I_{Ks}$ 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 $I_{Ks}$ contributes to human SAN pacemaker activity at all levels of autonomic tone.