Functional Role of the HCN4 Encoded ‘Funny Current’ in Human Sinus Node Pacemaker Cells

We recently reported patch clamp data on the voltage dependence of HCN4 channels expressed in human cardiomyocyte progenitor cells. Their half-activation voltage was 15 mV less negative than previously observed for the HCN4 encoded hyperpolarization-activated funny current’ $(I_{f})$ in isolated human sinus node cells. The time constant of (de)activation vs. voltage relationship showed a similar less negative voltage dependence as well as a 38% higher peak. We assessed the functional effects of these differences in $I_{f}$ kinetics in the Fabbri-Severi model of a single human sinus node pacemaker cell. The $+15\ mV$ shift in half-activation voltage per se resulted in a substantial increase in $I_{f}$, carrying 85 vs. 59% of the net diastolic depolarizing charge, and a 14% shortening of the cycle length from 813 to 699 ms. This effect was counteracted by the time constant vs. voltage relationship, which caused a slower activation of $I_{f}$ in the diastolic membrane potential range. The resulting net effect was a 5.4% shortening of the cycle length from 813 to 770 ms, with $I_{f}$ carrying 59% of the net diastolic charge, and limited effects on the autonomic modulation of pacing rate by isoprenaline and acetylcholine. We conclude that the absolute value of the half-activation voltage of $I_{f}$ may be less indicative of the functional role of $I_{f}$ than commonly assumed.