Downregulation of dendritic HCN channel gating in epilepsy is mediated by altered phosphorylation signaling
| Autor: | Sangwook Jung, Ignatius H. Lau, Lindsay N. Warner, James B. Bullis, Terrance D. Jones, Nicholas P. Poolos |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Calcineurin Inhibitors Cyclic Nucleotide-Gated Cation Channels Down-Regulation Magnesium Compounds Gating In Vitro Techniques Bicuculline Epileptogenesis p38 Mitogen-Activated Protein Kinases Article Membrane Potentials Rats Sprague-Dawley Downregulation and upregulation Seizures HCN channel medicine Animals Phosphorylation Protein kinase A CA1 Region Hippocampal Epilepsy biology Kinase Chemistry General Neuroscience Calcineurin Pyramidal Cells Dendrites Rats Disease Models Animal Chronic Disease biology.protein Neuroscience medicine.drug |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience. 30(19) |
| ISSN: | 1529-2401 |
| Popis: | 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 anin vitromodel of seizures (1 h in 0 Mg2+and 50 μmbicuculline at 35–37°C) reproduced the HCN channel gating change seenin vivo. Pharmacological inhibition of CaN or activation of p38 MAPK partially reversed thein vitroseizure-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 activityin vivoin 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. |
| Databáze: | OpenAIRE |
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