TY - GEN
T1 - Functional Role of the HCN4 Encoded 'Funny Current' in Human Sinus Node Pacemaker Cells
AU - Verkerk, Arie O.
AU - Wilders, Ronald
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85124739803&origin=inward
U2 - https://doi.org/10.23919/CinC53138.2021.9662853
DO - https://doi.org/10.23919/CinC53138.2021.9662853
M3 - Conference contribution
VL - 2021-September
T3 - Computing in Cardiology
BT - 2021 Computing in Cardiology, CinC 2021
PB - IEEE Computer Society
T2 - 2021 Computing in Cardiology, CinC 2021
Y2 - 13 September 2021 through 15 September 2021
ER -