HCN channels: Structure, cellular regulation and physiological function

Wahl‐Schott, Christian; Biel, Martin

doi:10.1007/s00018-008-8525-0

Cited by 372 publications

(417 citation statements)

References 245 publications

(273 reference statements)

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“…In dendrites, modifying the HCN channel alone had little effect on SKF83959-regulated neuronal excitability, which may be the result of a balance between excitatory and inhibitory effects. The difference between the responses of the soma and dendrites was most likely due to the much higher density of HCN channels in dendrites than in soma [27,37] . Moreover, we found that modifying the Na + channel or kdr channel alone facilitated depolarization block, consistent with previous studies [31] .…”

Section: Discussionmentioning

confidence: 99%

“…However, the specific role of HCN channels in SKF83959-regulated neuronal excitability is rather complex. It has been reported that the HCN channel can produce either excitatory (depolarizing the membrane) or inhibitory (decreasing the input resistance) effects on the excitability of pyramidal neurons [25][26][27][28] . In previous studies, the excitability of these neurons has been measured with the depolarized membrane potential compensated to the control level, which in some respects resulted in selectively neglecting the excitatory effect.…”

Section: Discussionmentioning

confidence: 99%

“…In previous studies, the excitability of these neurons has been measured with the depolarized membrane potential compensated to the control level, which in some respects resulted in selectively neglecting the excitatory effect. On the other hand, the gradient distribution of HCN channels in the soma and in the dendrite should also be considered [27] . In the present study, we examined the effects of SKF83959 in modulating HCN channels with or without membrane potential compensation.…”

Section: Discussionmentioning

confidence: 99%

“…Modeling of the effects of SKF83959 on EPSP temporal summa tion and synapse driven firing in the hippocampal pyramidal neuron Because the EPSP temporal summation along dendrites is very important in the induction of pyramidal neuronal firing [44] , and because many ion channels, including HCN channels, could affect this process [25,[27][28][29] , we examined the effects of SKF83959 on EPSP temporal summation and consequently on neuronal firing, using our mathematical model. One synapse bearing both AMPA and NMDA mechanisms was placed on one apical dendrite (210 µm from the soma).…”

Section: Skf83959 Facilitates Depolarization Block In Hippocampal Pyrmentioning

confidence: 99%

“…In regard to the HCN channel, the effect on neuronal excitability becomes more complex. The HCN channel alone could exert both excitatory (depolarizing the cell membrane) and inhibitory (decreasing input resistance) effects on neuronal excitability [25][26][27] . Because there has been only a limited number of pharmacological experiments and because the workings of these channels are complex, how the specific effect of SKF83959 on a single channel type contributes to the overall membrane excitability is not known.…”

Section: Introductionmentioning

confidence: 99%

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Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study

et al. 2014

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Aim: 3-Methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) have been shown to affect several types of voltage-dependent channels in hippocampal pyramidal neurons. The aim of this study was to determine how modulation of a individual type of the channels by SKF83959 contributes to the overall excitability of CA1 pyramidal neurons during either direct current injections or synaptic activation. Methods: Rat hippocampal slices were prepared. The kinetics of voltage-dependent Na + channels and neuronal excitability and depolarization block in CA1 pyramidal neurons were examined using whole-cell recording. A realistic mathematical model of hippocampal CA1 pyramidal neuron was used to simulate the effects of SKF83959 on neuronal excitability. Results: SKF83959 (50 μmol/L) shifted the inactivation curve of Na + current by 10.3 mV but had no effect on the activation curve in CA1 pyramidal neurons. The effects of SKF83959 on passive membrane properties, including a decreased input resistance and depolarized resting potential, predicted by our simulations were in agreement with the experimental data. The simulations showed that decreased excitability of the soma by SKF83959 (examined with current injection at the soma) was only observed when the membrane potential was compensated to the control levels, whereas the decreased dendritic excitability (examined with current injection at the dendrite) was found even without membrane potential compensation, which led to a decreased number of action potentials initiated at the soma. Moreover, SKF83959 significantly facilitated depolarization block in CA1 pyramidal neurons. SKF83959 decreased EPSP temporal summation and, of physiologically greater relevance, the synaptic-driven firing frequency. Conclusion: SKF83959 decreased the excitability of CA1 pyramidal neurons even though the drug caused the membrane potential depolarization. The results may reveal a partial mechanism for the drug's anti-Parkinsonian effects and may also suggest that SKF83959 has a potential antiepileptic effect.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Skf83959 Facilitates Depolarization Block In Hippocampal Pyrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study

et al. 2014

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Antiarrhythmic Drug Classification

Carnes

2009

Novel Therapeutic Targets for Antiarrhythmic Drugs

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Tau‐mediated synaptic dysfunction is coupled with HCN channelopathy

Goniotaki,

Tamagnini,

Biasetti

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONIn tauopathies, altered tau processing correlates with impairments in synaptic density and function. Changes in hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels contribute to disease‐associated abnormalities in multiple neurodegenerative diseases.METHODSTo investigate the link between tau and HCN channels, we performed histological, biochemical, ultrastructural, and functional analyses of hippocampal tissues from Alzheimer's disease (AD), age‐matched controls, Tau35 mice, and/or Tau35 primary hippocampal neurons.RESULTSExpression of specific HCN channels is elevated in post mortem AD hippocampus. Tau35 mice develop progressive abnormalities including increased phosphorylated tau, enhanced HCN channel expression, decreased dendritic branching, reduced synapse density, and vesicle clustering defects. Tau35 primary neurons show increased HCN channel expression enhanced hyperpolarization‐induced membrane voltage “sag” and changes in the frequency and kinetics of spontaneous excitatory postsynaptic currents.DISCUSSIONOur findings are consistent with a model in which pathological changes in tauopathies impact HCN channels to drive network‐wide structural and functional synaptic deficits.Highlights Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels are functionally linked to the development of tauopathy. Expression of specific HCN channels is elevated in the hippocampus in Alzheimer's disease and the Tau35 mouse model of tauopathy. Increased expression of HCN channels in Tau35 mice is accompanied by hyperpolarization‐induced membrane voltage “sag” demonstrating a detrimental effect of tau abnormalities on HCN channel function. Tau35 expression alters synaptic organization, causing a loosened vesicle clustering phenotype in Tau35 mice.

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HCN channels: Structure, cellular regulation and physiological function

Cited by 372 publications

References 245 publications

Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study

Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study

Antiarrhythmic Drug Classification

Tau‐mediated synaptic dysfunction is coupled with HCN channelopathy

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