Abstract
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’ <tex>$(I_{f})$</tex> 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 <tex>$I_{f}$</tex> kinetics in the Fabbri-Severi model of a single human sinus node pacemaker cell. The <tex>$+15\ mV$</tex> shift in half-activation voltage per se resulted in a substantial increase in <tex>$I_{f}$</tex>, 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 <tex>$I_{f}$</tex> 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 <tex>$I_{f}$</tex> 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 <tex>$I_{f}$</tex> may be less indicative of the functional role of <tex>$I_{f}$</tex> than commonly assumed.
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