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Articles, Neurobiology of Disease

Downregulation of Dendritic HCN Channel Gating in Epilepsy Is Mediated by Altered Phosphorylation Signaling

Sangwook Jung, James B. Bullis, Ignatius H. Lau, Terrance D. Jones, Lindsay N. Warner and Nicholas P. Poolos
Journal of Neuroscience 12 May 2010, 30 (19) 6678-6688; DOI: https://doi.org/10.1523/JNEUROSCI.1290-10.2010
Sangwook Jung
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James B. Bullis
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Ignatius H. Lau
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Terrance D. Jones
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Lindsay N. Warner
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Nicholas P. Poolos
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Abstract

The onset of spontaneous seizures in the pilocarpine model of epilepsy causes a hyperpolarized shift in the voltage-dependent activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated current (Ih) in CA1 hippocampal pyramidal neuron dendrites, contributing to neuronal hyperexcitability and possibly to epileptogenesis. However, the specific mechanisms by which spontaneous seizures cause downregulation of HCN channel gating are yet unknown. We asked whether the seizure-dependent downregulation of HCN channel gating was due to altered phosphorylation signaling mediated by the phosphatase calcineurin (CaN) or the kinase p38 mitogen-activated protein kinase (p38 MAPK). We first found that CaN inhibition upregulated HCN channel gating and reduced neuronal excitability under normal conditions, showing that CaN is a strong modulator of HCN channels. We then found that an in vitro model of seizures (1 h in 0 Mg2+ and 50 μm bicuculline at 35–37°C) reproduced the HCN channel gating change seen in vivo. Pharmacological inhibition of CaN or activation of p38 MAPK partially reversed the in vitro seizure-induced hyperpolarized shift in HCN channel gating, and the shift was fully reversed by the combination of CaN inhibition and p38 MAPK activation. We then demonstrated enhanced CaN activity as well as reduced p38 MAPK activity in vivo in the CA1 hippocampal area of chronically epileptic animals. Pharmacological reversal of these phosphorylation changes restored HCN channel gating downregulation and neuronal hyperexcitability in epileptic tissue to control levels. Together, these results suggest that alteration of two different phosphorylation pathways in epilepsy contributes to the downregulation of HCN channel gating, which consequently produces neuronal hyperexcitability and thus may be a target for novel antiepileptic therapies.

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The Journal of Neuroscience: 30 (19)
Journal of Neuroscience
Vol. 30, Issue 19
12 May 2010
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Downregulation of Dendritic HCN Channel Gating in Epilepsy Is Mediated by Altered Phosphorylation Signaling
Sangwook Jung, James B. Bullis, Ignatius H. Lau, Terrance D. Jones, Lindsay N. Warner, Nicholas P. Poolos
Journal of Neuroscience 12 May 2010, 30 (19) 6678-6688; DOI: 10.1523/JNEUROSCI.1290-10.2010

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Downregulation of Dendritic HCN Channel Gating in Epilepsy Is Mediated by Altered Phosphorylation Signaling
Sangwook Jung, James B. Bullis, Ignatius H. Lau, Terrance D. Jones, Lindsay N. Warner, Nicholas P. Poolos
Journal of Neuroscience 12 May 2010, 30 (19) 6678-6688; DOI: 10.1523/JNEUROSCI.1290-10.2010
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