Mechanisms of seizure-induced ‘transcriptional channelopathy’ of hyperpolarization-activated cyclic nucleotide gated (HCN) channels

Richichi, Cristina; Brewster, Amy L.; Bender, Roland A.; Simeone, Timothy A.; Zha, Qinqin; Yin, Hong; Weiss, John H.; Baram, Tallie Z.

doi:10.1016/j.nbd.2007.09.003

Cited by 80 publications

(75 citation statements)

References 53 publications

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“…It remains to be elucidated whether such dysregulation on a subset of ion channels is cause by a seizure-induced long-lasting deficiency of the transcriptional/translational machinery and whether these changes may lead to enhanced excitability of neuronal networks. The notion that acquired channelopathies may develop in the course of temporal lobe epilepsy is supported for recent findings in the pilocarpine model of epilepsy (Bernard et al, 2004;Dyhrfjeld-Johnsen and Soltesz, 2004;Hirose, 2006;Jung et al, 2007;Poolos, 2005;Richichi et al, 2007). For instance, it was recently reported that a progressive transcriptional channelopaty ("downregulation") of hyperpolarization-activated cation (HCN) channels occurs in dendrites of CA1 hippocampal pyramidal neurons after pilocarpine-induced SE (Jung et al, 2007).…”

Section: Discussionmentioning

confidence: 88%

“…down-regulation) remains to be determined, but it may probably involve changes in the transcription or translational machinery. For instance, it was proposed that the mechanisms for HCN1 reduction involved calciumpermeable AMPA receptor-mediated calcium influx, and subsequent activation of Calcium/ calmodulin-dependent protein kinase II (Richichi et al, 2007). Seizure-related changes in components of the transcriptional and translational machinery may contribute to dysregulation of genes and proteins in epilepsy.…”

Section: Discussionmentioning

confidence: 99%

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Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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In the hippocampus, BK channels are preferentially localized in presynaptic glutamatergic terminals including mossy fibers where they are thought to play an important role regulating excessive glutamate release during hyperactive states. Large conductance calcium-activated potassium channels (BK, MaxiK, Slo) have recently been implicated in the pathogenesis of genetic epilepsy. However, the role of BK channels in acquired mesial temporal lobe epilepsy (MTLE) remains unknown. Here we used immunohistochemistry, laser scanning confocal microscopy (LSCM), western immunoblotting and RT-PCR to investigate the expression pattern of the alpha-pore forming subunit of BK channels in the hippocampus and cortex of chronically epileptic rats obtained by the pilocarpine model of MTLE. All epileptic rats experiencing recurrent spontaneous seizures exhibited a significant down-regulation of BK channel immunostaining in the mossy fibers at the hilus and stratum lucidum of the CA3 area. Quantitative analysis of immunofluorescence signals by LSCM revealed a significant 47% reduction in BK channel in epileptic rats when compared to age-matched non-epileptic control rats. These data correlate with a similar reduction in BK channel protein levels and transcripts in the cortex and hippocampus. Our data indicate a seizure-related down-regulation of BK channels in chronically epileptic rats. Further functional assays are necessary to determine whether altered BK channel expression is an acquired channelopathy or a compensatory mechanism affecting the network excitability in MTLE. Moreover, seizure-mediated BK down-regulation may disturb neuronal excitability and presynaptic control at glutamatergic terminals triggering exaggerated glutamate release and seizures.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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“…Reduction of HCN1 channel expression is probably a transcriptionally regulated process that involves activation of calmodulin (CaM) kinase II and Ca 2ϩ entry via AMPA receptors (322). In contrast, upregulation of HCN2 was found to be independent of CaM kinase II (322). The consequences of up-and downregulation of HCN channel subunits may be more complex than originally expected.…”

Section: Epilepsymentioning

confidence: 96%

“…The mechanism underlying changes in HCN channel expression levels in response to seizures is unclear. Reduction of HCN1 channel expression is probably a transcriptionally regulated process that involves activation of calmodulin (CaM) kinase II and Ca 2ϩ entry via AMPA receptors (322). In contrast, upregulation of HCN2 was found to be independent of CaM kinase II (322).…”

Section: Epilepsymentioning

confidence: 99%

Hyperpolarization-Activated Cation Channels: From Genes to Function

Biel

Wahl‐Schott²,

Michalakis³

et al. 2009

Physiological Reviews

871

974

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a small subfamily of proteins within the superfamily of pore-loop cation channels. In mammals, the HCN channel family comprises four members (HCN1-4) that are expressed in heart and nervous system. The current produced by HCN channels has been known as Ih (or If or Iq). Ih has also been designated as pacemaker current, because it plays a key role in controlling rhythmic activity of cardiac pacemaker cells and spontaneously firing neurons. Extensive studies over the last decade have provided convincing evidence that Ih is also involved in a number of basic physiological processes that are not directly associated with rhythmicity. Examples for these non-pacemaking functions of Ih are the determination of the resting membrane potential, dendritic integration, synaptic transmission, and learning. In this review we summarize recent insights into the structure, function, and cellular regulation of HCN channels. We also discuss in detail the different aspects of HCN channel physiology in the heart and nervous system. To this end, evidence on the role of individual HCN channel types arising from the analysis of HCN knockout mouse models is discussed. Finally, we provide an overview of the impact of HCN channels on the pathogenesis of several diseases and discuss recent attempts to establish HCN channels as drug targets.

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“…One-third of the protein sample was reserved (Ϫ80°C; representing the total pool of both surface and intracellular protein), and the remaining two-thirds were precipitated with ImmunoPure immobilized Streptavidin beads (Pierce) at 4°C. Western blots were performed as previously described (16,17), using the following primary antibodies: monoclonal mouse anti-HCN1 (1:500; NeuroMab), rabbit anti-HCN2 (1:2000; Alomone), rabbit antiKv4.2 (1:2000; Abcam), anti-actin (1:200,000), and anti-synaptophysin (1:200,000). Signal intensities were analyzed using ImageTool software (University of Texas Health Science Center).…”

Section: Hippocampal Organotypic Slice Cultures and Biotinylation Assaymentioning

confidence: 99%

Trafficking and Surface Expression of Hyperpolarization-activated Cyclic Nucleotide-gated Channels in Hippocampal Neurons

Noam

Zha

Phan

et al. 2010

Journal of Biological Chemistry

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels mediate the hyperpolarization-activated current I h and thus play important roles in the regulation of brain excitability. The subcellular distribution pattern of the HCN channels influences the effects that they exert on the properties and activity of neurons. However, little is known about the mechanisms that control HCN channel trafficking to subcellular compartments or that regulate their surface expression. Here we studied the dynamics of HCN channel trafficking in hippocampal neurons using dissociated cultures coupled with time lapse imaging of fluorophore-fused HCN channels. HCN1-green fluorescence protein (HCN1-GFP) channels resided in vesicle-like organelles that moved in distinct patterns along neuronal dendrites, and these properties were isoform-specific. HCN1 trafficking required intact actin and tubulin and was rapidly inhibited by activation of either NMDA or AMPA-type ionotropic glutamate receptors in a calcium-dependent manner. Glutamate-induced inhibition of the movement of HCN1-GFP-expressing puncta was associated with increased surface expression of both native and transfected HCN1 channels, and this surface expression was accompanied by augmented I h . Taken together, the results reveal the highly dynamic nature of HCN1 channel trafficking in hippocampal neurons and provide a novel potential mechanism for rapid regulation of I h , and hence of neuronal properties, via alterations of HCN1 trafficking and surface expression.The ion channel repertoire of neurons contributes critically to the regulation of neuronal activity. The response of a neuron to an incoming input depends (among other factors) on the molecular composition of its ion channels, their relative abundance, their subcellular location, and the fine tuning of their biophysical properties (1, 2). Mechanisms that control the function, expression levels, and/or subcellular localization of ion channels can influence neuronal function in many ways and at different time scales (1, 2). During the past decade, dynamic regulations of ion channel trafficking and surface expression have emerged as pivotal mechanisms in many forms of neuronal plasticity. However, whereas substantial advances have been made in uncovering the cellular dynamics of synaptic ion channel trafficking (3), less is known about the transport of extrasynaptic dendritic channels that contribute to intrinsic excitability.Hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 channels are a family of voltage-gated ion channels that mediate a non-selective cationic current named I h . Unlike other voltage-gated ion channels, members of the HCN family are activated upon hyperpolarization of the cell membrane, and this unusual feature endows them with unique and versatile roles in the regulation of neuronal excitability (4). The subcellular distribution of HCN channels varies in different cell types and brain regions and is important for determining the effects that these channels exert on neuronal excita...

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Mechanisms of seizure-induced ‘transcriptional channelopathy’ of hyperpolarization-activated cyclic nucleotide gated (HCN) channels

Cited by 80 publications

References 53 publications

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Hyperpolarization-Activated Cation Channels: From Genes to Function

Trafficking and Surface Expression of Hyperpolarization-activated Cyclic Nucleotide-gated Channels in Hippocampal Neurons

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