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Mode shifts in the voltage gating of the mouse and human HCN2 and HCN4 channels.
Elinder F
,
Männikkö R
,
Pandey S
,
Larsson HP
.
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Hyperpolarization-activated, cyclic-nucleotide-gated (HCN) channels regulate pacemaker activity in the heart and the brain. Previously, we showed that spHCN and HCN1 channels undergo mode shifts in their voltage dependences, shifting the conductance versus voltage curves by more than +50 mV when measured from a hyperpolarized potential compared to a depolarized potential. In addition, the kinetics of the ionic currents changed in parallel to these voltage shifts. In the studies reported here, we tested whether slower cardiac HCN channels also display similar mode shifts. We found that HCN2 and HCN4 channels expressed in oocytes from the frog Xenopus laevis do not display the activation kinetic changes that we observed in spHCN and HCN1. However, HCN2 and HCN4 channels display changes in their tail currents, suggesting that these channels also undergo mode shifts and that the conformational changes underlying the mode shifts are due to conserved aspects of HCN channels. With computer modelling, we show that in channels with relatively slow opening kinetics and fast mode-shift transitions, such as HCN2 and HCN4 channels, the mode shift effects are not readily observable, except in the tail kinetics. Computer simulations of sino-atrial node action potentials suggest that the HCN2 channel, together with the HCN1 channel, are important regulators of the heart firing frequency and that the mode shift is an important property to prevent arrhythmic firing. We conclude that although all HCN channels appear to undergo mode shifts - and thus may serve to prevent arrhythmic firing - it is mainly observable in ionic currents from HCN channels with faster kinetics.
Altomare,
Integrated allosteric model of voltage gating of HCN channels.
2001, Pubmed
Altomare,
Integrated allosteric model of voltage gating of HCN channels.
2001,
Pubmed
Altomare,
Heteromeric HCN1-HCN4 channels: a comparison with native pacemaker channels from the rabbit sinoatrial node.
2003,
Pubmed
Azene,
Non-equilibrium behavior of HCN channels: insights into the role of HCN channels in native and engineered pacemakers.
2005,
Pubmed
,
Xenbase
Baruscotti,
Physiology and pharmacology of the cardiac pacemaker ("funny") current.
2005,
Pubmed
Chen,
Functional roles of charged residues in the putative voltage sensor of the HCN2 pacemaker channel.
2000,
Pubmed
,
Xenbase
Chen,
Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide.
2001,
Pubmed
,
Xenbase
DiFrancesco,
Pacemaker mechanisms in cardiac tissue.
1993,
Pubmed
HODGKIN,
A quantitative description of membrane current and its application to conduction and excitation in nerve.
1952,
Pubmed
Hahin,
Removal of inactivation causes time-invariant sodium current decays.
1988,
Pubmed
Halliwell,
Voltage-clamp analysis of muscarinic excitation in hippocampal neurons.
1982,
Pubmed
Larsson,
A conserved glutamate is important for slow inactivation in K+ channels.
2000,
Pubmed
,
Xenbase
Ludwig,
A family of hyperpolarization-activated mammalian cation channels.
1998,
Pubmed
Ludwig,
Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2.
2003,
Pubmed
Ludwig,
Structure and function of cardiac pacemaker channels.
1999,
Pubmed
López-Barneo,
Effects of external cations and mutations in the pore region on C-type inactivation of Shaker potassium channels.
1993,
Pubmed
,
Xenbase
Magee,
Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons.
1998,
Pubmed
Moroni,
Hyperpolarization-activated cyclic nucleotide-gated channel 1 is a molecular determinant of the cardiac pacemaker current I(f).
2001,
Pubmed
Männikkö,
Hysteresis in the voltage dependence of HCN channels: conversion between two modes affects pacemaker properties.
2005,
Pubmed
,
Xenbase
Männikkö,
Voltage-sensing mechanism is conserved among ion channels gated by opposite voltages.
2002,
Pubmed
,
Xenbase
Nolan,
The hyperpolarization-activated HCN1 channel is important for motor learning and neuronal integration by cerebellar Purkinje cells.
2003,
Pubmed
Olcese,
Correlation between charge movement and ionic current during slow inactivation in Shaker K+ channels.
1997,
Pubmed
,
Xenbase
Pape,
Queer current and pacemaker: the hyperpolarization-activated cation current in neurons.
1996,
Pubmed
Robinson,
Hyperpolarization-activated cation currents: from molecules to physiological function.
2003,
Pubmed
Santoro,
The HCN gene family: molecular basis of the hyperpolarization-activated pacemaker channels.
1999,
Pubmed
Santoro,
Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain.
1998,
Pubmed
,
Xenbase
Schulze-Bahr,
Pacemaker channel dysfunction in a patient with sinus node disease.
2003,
Pubmed
Shi,
Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues.
1999,
Pubmed
Shin,
Inactivation in HCN channels results from reclosure of the activation gate: desensitization to voltage.
2004,
Pubmed
Tokimasa,
Cyclic AMP regulates an inward rectifying sodium-potassium current in dissociated bull-frog sympathetic neurones.
1990,
Pubmed
Ueda,
Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia.
2004,
Pubmed
Ulens,
Functional heteromerization of HCN1 and HCN2 pacemaker channels.
2001,
Pubmed
,
Xenbase
Wang,
Activity-dependent regulation of HCN pacemaker channels by cyclic AMP: signaling through dynamic allosteric coupling.
2002,
Pubmed
,
Xenbase
Zagotta,
Shaker potassium channel gating. II: Transitions in the activation pathway.
1994,
Pubmed
,
Xenbase
Zhang,
Mathematical models of action potentials in the periphery and center of the rabbit sinoatrial node.
2000,
Pubmed
