title: Mechanisms of seizure-induced 'transcriptional channelopathy' of hyperpolarization-activated cyclic nucleotide gated (HCN) channels.
abstract: Epilepsy may result from abnormal function of ion channels, such as those caused by genetic mutations. Recently, pathological alterations of the expression or localization of normal channels have been implicated in epilepsy generation, and termed 'acquired channelopathies'. Altered expression levels of the HCN channels - that conduct the hyperpolarization-activated current, I(h) - have been demonstrated in hippocampus of patients with severe temporal lobe epilepsy as well as in animal models of temporal lobe and absence epilepsies. Here we probe the mechanisms for the altered expression of HCN channels which is provoked by seizures. In organotypic hippocampal slice cultures, seizure-like events selectively reduced HCN type 1 channel expression and increased HCN2 mRNA levels, as occurs in vivo. The mechanisms for HCN1 reduction involved Ca(2+)-permeable AMPA receptor-mediated Ca(2+) influx, and subsequent activation of Ca(2+)/calmodulin-dependent protein kinase II. In contrast, upregulation of HCN2 expression was independent of these processes. The data demonstrate an orchestrated program for seizure-evoked transcriptional channelopathy involving the HCN channels that may contribute to certain epilepsies.
authors.affiliation: Department Anatomy and Neurobiology, University of California, Irvine, CA 92697-4475, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Richichi
authors.forename: Amy L
authors.initials: AL
authors.lastname: Brewster
authors.forename: Roland A
authors.initials: RA
authors.lastname: Bender
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Simeone
authors.forename: Qinqin
authors.initials: Q
authors.lastname: Zha
authors.forename: Hong Z
authors.initials: HZ
authors.lastname: Yin
authors.forename: John H
authors.initials: JH
authors.lastname: Weiss
authors.forename: Tallie Z
authors.initials: TZ
authors.lastname: Baram
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D020287:In Situ Nick-End Labeling / Q000379:methods; D066298:In Vitro Techniques; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D007608:Kainic Acid; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000473:pathology*
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; C578667:Hcn1 protein, rat; C578712:Hcn2 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels; D015763:2-Amino-5-phosphonovalerate; D007608:Kainic Acid; D002118:Calcium