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Hysteresis in the voltage dependence of HCN channels: conversion between two modes affects pacemaker properties.

Männikkö R, Pandey S, Larsson HP, Elinder F - J. Gen. Physiol. (2005)

Bottom Line: For example, both the gating charge versus voltage curve, Q(V), and the conductance versus voltage curve, G(V), are shifted by about +60 mV when measured from a hyperpolarized holding potential compared with a depolarized holding potential.Mammalian HCN1 channels display similar effects in their ionic currents, suggesting that the mammalian HCN channels also undergo voltage hysteresis.Computer simulations suggest that voltage hysteresis in HCN channels decreases the risk of arrhythmia in pacemaker cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, The Nobel Institute for Neurophysiology, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
Hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels are important for rhythmic activity in the brain and in the heart. In this study, using ionic and gating current measurements, we show that cloned spHCN channels undergo a hysteresis in their voltage dependence during normal gating. For example, both the gating charge versus voltage curve, Q(V), and the conductance versus voltage curve, G(V), are shifted by about +60 mV when measured from a hyperpolarized holding potential compared with a depolarized holding potential. In addition, the kinetics of the tail current and the activation current change in parallel to the voltage shifts of the Q(V) and G(V) curves. Mammalian HCN1 channels display similar effects in their ionic currents, suggesting that the mammalian HCN channels also undergo voltage hysteresis. We propose a model in which HCN channels transit between two modes. The voltage dependence in the two modes is shifted relative to each other, and the occupancy of the two modes depends on the previous activation of the channel. The shifts in the voltage dependence are fast (tau approximately 100 ms) and are not accompanied by any apparent inactivation. In HCN1 channels, the shift in voltage dependence is slower in a 100 mM K extracellular solution compared with a 1 mM K solution. Based on these findings, we suggest that molecular conformations similar to slow (C-type) inactivation of K channels underlie voltage hysteresis in HCN channels. The voltage hysteresis results in HCN channels displaying different voltage dependences during different phases in the pacemaker cycle. Computer simulations suggest that voltage hysteresis in HCN channels decreases the risk of arrhythmia in pacemaker cells.

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20-state extension of the four-state model. (A) Each closed and open state in the four-state model have been expanded to five states, representing 0, 1, 2, 3, or 4 S4s activated (moved inward). The channels would mainly open from the states with all S4s activated and close from the states with all S4s deactivated (moved outward). Hysteresis mainly affects the α and β rates. (B and C) Simulations of tail currents after short (continuous line) and long (dotted line) activation prepulses, using a simplified version of the model in A. All channels were assumed to be in Oi4 after short prepulses and in Oii4 after long prepulses. For simplicity, all rate constants were assumed to be zero except for β and λ. The closing rate λ is set to 25 ms−1 for all traces. β was assumed to change 2.5-fold between mode I and mode II. (B) Tail currents at +50 mV, where β = 75 ms−1 in mode I. (C) Tail currents at −15 mV, where β = 25 ms−1 in mode I. These simple simulations are not supposed to be seen as a quantitative fit to our recordings, but only as a qualitative suggestion that the slowing of the tails and the development of a delay in the tails can be due to voltage hysteresis. For example, the voltage dependence in these simulations was assumed to be only in the closed–closed transitions and open–open transitions, not in the open–closed transitions. Most likely, the open–closed transitions are also voltage dependent (Altomare et al., 2001).
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fig20: 20-state extension of the four-state model. (A) Each closed and open state in the four-state model have been expanded to five states, representing 0, 1, 2, 3, or 4 S4s activated (moved inward). The channels would mainly open from the states with all S4s activated and close from the states with all S4s deactivated (moved outward). Hysteresis mainly affects the α and β rates. (B and C) Simulations of tail currents after short (continuous line) and long (dotted line) activation prepulses, using a simplified version of the model in A. All channels were assumed to be in Oi4 after short prepulses and in Oii4 after long prepulses. For simplicity, all rate constants were assumed to be zero except for β and λ. The closing rate λ is set to 25 ms−1 for all traces. β was assumed to change 2.5-fold between mode I and mode II. (B) Tail currents at +50 mV, where β = 75 ms−1 in mode I. (C) Tail currents at −15 mV, where β = 25 ms−1 in mode I. These simple simulations are not supposed to be seen as a quantitative fit to our recordings, but only as a qualitative suggestion that the slowing of the tails and the development of a delay in the tails can be due to voltage hysteresis. For example, the voltage dependence in these simulations was assumed to be only in the closed–closed transitions and open–open transitions, not in the open–closed transitions. Most likely, the open–closed transitions are also voltage dependent (Altomare et al., 2001).

Mentions: We have mainly used a simple four-state model, since it can qualitatively describe most of the experimental data presented in this paper. A natural expansion of the four-state model would include four additional closed states and four additional open states for each mode, by allowing S4 in each subunit to move independently in each state. The resulting 20-state model (Fig. 20 A) would be able to generate the voltage hysteresis described in this paper, in addition to the sigmoidicity of the activation and deactivation currents. Determining a unique set of parameters for the 20-state model would require significantly more kinetic data. We have, therefore, left the development of this model for a future study. However, we point out now that, with this simple extension of the four-state model to the 20-state model, voltage hysteresis can generate the qualitatively different tail currents shown in HCN channels (Fig. 20).


Hysteresis in the voltage dependence of HCN channels: conversion between two modes affects pacemaker properties.

Männikkö R, Pandey S, Larsson HP, Elinder F - J. Gen. Physiol. (2005)

20-state extension of the four-state model. (A) Each closed and open state in the four-state model have been expanded to five states, representing 0, 1, 2, 3, or 4 S4s activated (moved inward). The channels would mainly open from the states with all S4s activated and close from the states with all S4s deactivated (moved outward). Hysteresis mainly affects the α and β rates. (B and C) Simulations of tail currents after short (continuous line) and long (dotted line) activation prepulses, using a simplified version of the model in A. All channels were assumed to be in Oi4 after short prepulses and in Oii4 after long prepulses. For simplicity, all rate constants were assumed to be zero except for β and λ. The closing rate λ is set to 25 ms−1 for all traces. β was assumed to change 2.5-fold between mode I and mode II. (B) Tail currents at +50 mV, where β = 75 ms−1 in mode I. (C) Tail currents at −15 mV, where β = 25 ms−1 in mode I. These simple simulations are not supposed to be seen as a quantitative fit to our recordings, but only as a qualitative suggestion that the slowing of the tails and the development of a delay in the tails can be due to voltage hysteresis. For example, the voltage dependence in these simulations was assumed to be only in the closed–closed transitions and open–open transitions, not in the open–closed transitions. Most likely, the open–closed transitions are also voltage dependent (Altomare et al., 2001).
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Related In: Results  -  Collection

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fig20: 20-state extension of the four-state model. (A) Each closed and open state in the four-state model have been expanded to five states, representing 0, 1, 2, 3, or 4 S4s activated (moved inward). The channels would mainly open from the states with all S4s activated and close from the states with all S4s deactivated (moved outward). Hysteresis mainly affects the α and β rates. (B and C) Simulations of tail currents after short (continuous line) and long (dotted line) activation prepulses, using a simplified version of the model in A. All channels were assumed to be in Oi4 after short prepulses and in Oii4 after long prepulses. For simplicity, all rate constants were assumed to be zero except for β and λ. The closing rate λ is set to 25 ms−1 for all traces. β was assumed to change 2.5-fold between mode I and mode II. (B) Tail currents at +50 mV, where β = 75 ms−1 in mode I. (C) Tail currents at −15 mV, where β = 25 ms−1 in mode I. These simple simulations are not supposed to be seen as a quantitative fit to our recordings, but only as a qualitative suggestion that the slowing of the tails and the development of a delay in the tails can be due to voltage hysteresis. For example, the voltage dependence in these simulations was assumed to be only in the closed–closed transitions and open–open transitions, not in the open–closed transitions. Most likely, the open–closed transitions are also voltage dependent (Altomare et al., 2001).
Mentions: We have mainly used a simple four-state model, since it can qualitatively describe most of the experimental data presented in this paper. A natural expansion of the four-state model would include four additional closed states and four additional open states for each mode, by allowing S4 in each subunit to move independently in each state. The resulting 20-state model (Fig. 20 A) would be able to generate the voltage hysteresis described in this paper, in addition to the sigmoidicity of the activation and deactivation currents. Determining a unique set of parameters for the 20-state model would require significantly more kinetic data. We have, therefore, left the development of this model for a future study. However, we point out now that, with this simple extension of the four-state model to the 20-state model, voltage hysteresis can generate the qualitatively different tail currents shown in HCN channels (Fig. 20).

Bottom Line: For example, both the gating charge versus voltage curve, Q(V), and the conductance versus voltage curve, G(V), are shifted by about +60 mV when measured from a hyperpolarized holding potential compared with a depolarized holding potential.Mammalian HCN1 channels display similar effects in their ionic currents, suggesting that the mammalian HCN channels also undergo voltage hysteresis.Computer simulations suggest that voltage hysteresis in HCN channels decreases the risk of arrhythmia in pacemaker cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, The Nobel Institute for Neurophysiology, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
Hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels are important for rhythmic activity in the brain and in the heart. In this study, using ionic and gating current measurements, we show that cloned spHCN channels undergo a hysteresis in their voltage dependence during normal gating. For example, both the gating charge versus voltage curve, Q(V), and the conductance versus voltage curve, G(V), are shifted by about +60 mV when measured from a hyperpolarized holding potential compared with a depolarized holding potential. In addition, the kinetics of the tail current and the activation current change in parallel to the voltage shifts of the Q(V) and G(V) curves. Mammalian HCN1 channels display similar effects in their ionic currents, suggesting that the mammalian HCN channels also undergo voltage hysteresis. We propose a model in which HCN channels transit between two modes. The voltage dependence in the two modes is shifted relative to each other, and the occupancy of the two modes depends on the previous activation of the channel. The shifts in the voltage dependence are fast (tau approximately 100 ms) and are not accompanied by any apparent inactivation. In HCN1 channels, the shift in voltage dependence is slower in a 100 mM K extracellular solution compared with a 1 mM K solution. Based on these findings, we suggest that molecular conformations similar to slow (C-type) inactivation of K channels underlie voltage hysteresis in HCN channels. The voltage hysteresis results in HCN channels displaying different voltage dependences during different phases in the pacemaker cycle. Computer simulations suggest that voltage hysteresis in HCN channels decreases the risk of arrhythmia in pacemaker cells.

Show MeSH
Related in: MedlinePlus