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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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Voltage ramps. (A) Conductance of spHCN channels during voltage ramps from −10 mV to −100 mV, and back to −10 mV, using different ramp speeds. 100-K bath solution. The conductance was normalized to 1 at −100 mV. (B) Conductance of Shaker channels during voltage ramps from −80 mV to +20 mV, and back to −80 mV, using different ramp speeds. The conductance was normalized to 1 at +20 mV. 1-K bath solution. Note that with a slower ramp speed, voltage hysteresis decreases in Shaker channels, whereas it increases in spHCN channels. With slower voltage ramps, the two limbs in the G(V) curve approach each other in Kv channels, but in HCN channels, the two limbs are well separated even for slow ramps. (C–F) Computer simulations of voltage-ramp currents for the models in Fig. 5. The ramp speed is 125, 250, 500, 1,000, and 2,000 mV/s (from periphery to center). (G and H) Hysteresis measured as the voltage separation between the upward and downward limbs at 50% relative conductance (relative to the conductance at −100 mV).
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fig11: Voltage ramps. (A) Conductance of spHCN channels during voltage ramps from −10 mV to −100 mV, and back to −10 mV, using different ramp speeds. 100-K bath solution. The conductance was normalized to 1 at −100 mV. (B) Conductance of Shaker channels during voltage ramps from −80 mV to +20 mV, and back to −80 mV, using different ramp speeds. The conductance was normalized to 1 at +20 mV. 1-K bath solution. Note that with a slower ramp speed, voltage hysteresis decreases in Shaker channels, whereas it increases in spHCN channels. With slower voltage ramps, the two limbs in the G(V) curve approach each other in Kv channels, but in HCN channels, the two limbs are well separated even for slow ramps. (C–F) Computer simulations of voltage-ramp currents for the models in Fig. 5. The ramp speed is 125, 250, 500, 1,000, and 2,000 mV/s (from periphery to center). (G and H) Hysteresis measured as the voltage separation between the upward and downward limbs at 50% relative conductance (relative to the conductance at −100 mV).

Mentions: The conductance of spHCN channels displayed voltage hysteresis in response to slow voltage ramps (shown in Fig. 11 A). It is important to note that any voltage-dependent channel displays hysteresis when the voltage is ramped faster than the opening kinetics of the channel and that the hysteresis decreases for very slow ramps. However, the hysteresis in spHCN channels is qualitatively different from the hysteresis in other voltage-gated ion channels. In the Shaker Kv channel, we found that the hysteresis monotonically decreased with a decreasing ramp speed for all ramp rates tested (Fig. 11 B). In contrast, in spHCN channels, the hysteresis did not decrease and, for some ramp speeds, even appeared to increase with decreasing ramp speed (Fig. 11 A). For even slower ramp speeds, the hysteresis did decrease for spHCN, but even for a ramp speed as slow as 10 mV/s, there was a clear hysteresis. However, in response to very slow voltage ramps, we expect HCN channels not to display any voltage hysteresis because they have time to reach equilibrium at all voltages.


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)

Voltage ramps. (A) Conductance of spHCN channels during voltage ramps from −10 mV to −100 mV, and back to −10 mV, using different ramp speeds. 100-K bath solution. The conductance was normalized to 1 at −100 mV. (B) Conductance of Shaker channels during voltage ramps from −80 mV to +20 mV, and back to −80 mV, using different ramp speeds. The conductance was normalized to 1 at +20 mV. 1-K bath solution. Note that with a slower ramp speed, voltage hysteresis decreases in Shaker channels, whereas it increases in spHCN channels. With slower voltage ramps, the two limbs in the G(V) curve approach each other in Kv channels, but in HCN channels, the two limbs are well separated even for slow ramps. (C–F) Computer simulations of voltage-ramp currents for the models in Fig. 5. The ramp speed is 125, 250, 500, 1,000, and 2,000 mV/s (from periphery to center). (G and H) Hysteresis measured as the voltage separation between the upward and downward limbs at 50% relative conductance (relative to the conductance at −100 mV).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2234019&req=5

fig11: Voltage ramps. (A) Conductance of spHCN channels during voltage ramps from −10 mV to −100 mV, and back to −10 mV, using different ramp speeds. 100-K bath solution. The conductance was normalized to 1 at −100 mV. (B) Conductance of Shaker channels during voltage ramps from −80 mV to +20 mV, and back to −80 mV, using different ramp speeds. The conductance was normalized to 1 at +20 mV. 1-K bath solution. Note that with a slower ramp speed, voltage hysteresis decreases in Shaker channels, whereas it increases in spHCN channels. With slower voltage ramps, the two limbs in the G(V) curve approach each other in Kv channels, but in HCN channels, the two limbs are well separated even for slow ramps. (C–F) Computer simulations of voltage-ramp currents for the models in Fig. 5. The ramp speed is 125, 250, 500, 1,000, and 2,000 mV/s (from periphery to center). (G and H) Hysteresis measured as the voltage separation between the upward and downward limbs at 50% relative conductance (relative to the conductance at −100 mV).
Mentions: The conductance of spHCN channels displayed voltage hysteresis in response to slow voltage ramps (shown in Fig. 11 A). It is important to note that any voltage-dependent channel displays hysteresis when the voltage is ramped faster than the opening kinetics of the channel and that the hysteresis decreases for very slow ramps. However, the hysteresis in spHCN channels is qualitatively different from the hysteresis in other voltage-gated ion channels. In the Shaker Kv channel, we found that the hysteresis monotonically decreased with a decreasing ramp speed for all ramp rates tested (Fig. 11 B). In contrast, in spHCN channels, the hysteresis did not decrease and, for some ramp speeds, even appeared to increase with decreasing ramp speed (Fig. 11 A). For even slower ramp speeds, the hysteresis did decrease for spHCN, but even for a ramp speed as slow as 10 mV/s, there was a clear hysteresis. However, in response to very slow voltage ramps, we expect HCN channels not to display any voltage hysteresis because they have time to reach equilibrium at all voltages.

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