TY - JOUR
T1 - Non-equilibrium behavior of HCN channels
T2 - Insights into the role of HCN channels in native and engineered pacemakers
AU - Azene, Ezana M.
AU - Xue, Tian
AU - Marbán, Eduardo
AU - Tomaselli, Gordon F.
AU - Li, Ronald A.
N1 - Funding Information:
This work was supported by a grant from the NIH (R01 HL-52768 and HL72857 to R.A.L.). R.A.L. received salary support from the Cardiac Arrhythmias Research and Education Foundation, Inc. during the tenure of this project.
PY - 2005/8/1
Y1 - 2005/8/1
N2 - Objective: If, encoded by the hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channel gene family, modulates cardiac pacing. During cardiac pacing, changes in membrane potential are rapid, preventing the very slow HCN channels from reaching equilibrium. Here, we examined the properties of HCN channels under non-equilibrium conditions to shed insight into how different HCN isoforms contribute to cardiac pacing. Methods and results: HCN1, 2 and 4 channels were heterologously expressed in Xenopus laevis oocytes or mammalian Cos7 cells and subjected to voltage clamp. We found that HCN1 channel activation (V1/2) depended strongly on the holding potential (VH) for short (100 ms; V1/2 = - 118 mV, - 78 mV and - 19 mV for VH = + 70, - 75 and - 140 mV, respectively, in Xenopus oocytes) but not long (300-ms) test-pulses, hinting that shifts of V 1/2 under non-equilibrium conditions may alter the impact of I f in different phases of the cardiac circle. Consistent with this notion, when a train of SA nodal-like action potentials was applied in voltage-clamp experiments, HCN1 exhibited pronounced current-voltage (IV)-hysteresis. Using computational modeling, we demonstrate that the intrinsically sluggish HCN1 activation kinetics underlie their IV-hysteretic behavior and do not hinder the ability to modulate cardiac pacing. By contrast, HCN4 did not exhibit IV-hysteresis. This difference can be attributed to the relatively large activation time constant and markedly delayed onsets of time-dependent HCN4 currents. Indeed, HCN2 channels, which have intermediate activation time constants and delays, displayed and intermediate hysteretic phenotype. Conclusion: We conclude that non-equilibrium properties of HCN channels contribute to cardiac pacing. These results provide insight for tuning the firing rate of endogenous and induced pacemakers using engineered HCN constructs with distinct gating phenotypes.
AB - Objective: If, encoded by the hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channel gene family, modulates cardiac pacing. During cardiac pacing, changes in membrane potential are rapid, preventing the very slow HCN channels from reaching equilibrium. Here, we examined the properties of HCN channels under non-equilibrium conditions to shed insight into how different HCN isoforms contribute to cardiac pacing. Methods and results: HCN1, 2 and 4 channels were heterologously expressed in Xenopus laevis oocytes or mammalian Cos7 cells and subjected to voltage clamp. We found that HCN1 channel activation (V1/2) depended strongly on the holding potential (VH) for short (100 ms; V1/2 = - 118 mV, - 78 mV and - 19 mV for VH = + 70, - 75 and - 140 mV, respectively, in Xenopus oocytes) but not long (300-ms) test-pulses, hinting that shifts of V 1/2 under non-equilibrium conditions may alter the impact of I f in different phases of the cardiac circle. Consistent with this notion, when a train of SA nodal-like action potentials was applied in voltage-clamp experiments, HCN1 exhibited pronounced current-voltage (IV)-hysteresis. Using computational modeling, we demonstrate that the intrinsically sluggish HCN1 activation kinetics underlie their IV-hysteretic behavior and do not hinder the ability to modulate cardiac pacing. By contrast, HCN4 did not exhibit IV-hysteresis. This difference can be attributed to the relatively large activation time constant and markedly delayed onsets of time-dependent HCN4 currents. Indeed, HCN2 channels, which have intermediate activation time constants and delays, displayed and intermediate hysteretic phenotype. Conclusion: We conclude that non-equilibrium properties of HCN channels contribute to cardiac pacing. These results provide insight for tuning the firing rate of endogenous and induced pacemakers using engineered HCN constructs with distinct gating phenotypes.
KW - Gating
KW - HCN channel
KW - Hysteresis
KW - Ion channel
KW - Non-equilibrium
KW - Pacemaker
KW - Sino atrial node
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U2 - 10.1016/j.cardiores.2005.03.006
DO - 10.1016/j.cardiores.2005.03.006
M3 - Article
C2 - 16005302
AN - SCOPUS:21744440389
SN - 0008-6363
VL - 67
SP - 263
EP - 273
JO - Cardiovascular research
JF - Cardiovascular research
IS - 2
ER -