title: Molecular and functional changes in voltage-dependent Na(+) channels following pilocarpine-induced status epilepticus in rat dentate granule cells.
abstract: Status epilepticus (S.E.) is known to lead to a large number of changes in the expression of voltage-dependent ion channels and neurotransmitter receptors. In the present study, we examined whether an episode of S.E. induced by pilocarpine in vivo alters functional properties and expression of voltage-gated Na(+) channels in dentate granule cells (DGCs) of the rat hippocampus. Using patch-clamp recordings in isolated DGCs, we show that the voltage-dependent inactivation curve is significantly shifted toward depolarizing potentials following S.E. (half-maximal inactivation at -43.2+/-0.6 mV) when compared with control rats (-48.2+/-0.8 mV, P<0.0001). The voltage-dependent activation curve is significantly shifted to more negative potentials following S.E., with half-maximal activation at -28.6+/-0.8 mV compared with -25.8+/-0.9 mV in control animals (P<0.05). The changes in voltage dependence resulted in an augmented window current due to increased overlap between the activation and inactivation curve. In contrast to Na(+) channel voltage-dependence, S.E. caused no changes in the kinetics of fast or slow recovery from inactivation. The functional changes were accompanied by altered expression of Na(+) channel subunits measured by real-time reverse transcription-polymerase chain reaction in dentate gyrus microslices. We investigated expression of the pore-forming alpha subunits Na(v)1.1-Na(v)1.3 and Na(v)1.5-Na(v)1.6, in addition to the accessory subunits beta(1) and beta(2). The Na(v)1.2 and Na(v)1.6 subunit as well as the beta(1) subunit were persistently down-regulated up to 30 days following S.E. The beta(2) subunit was transiently down-regulated on the first and third day following S.E. These results indicate that differential changes in Na(+) channel subunit expression occur in concert with functional changes. Because coexpression of beta subunits is known to robustly shift the voltage dependence of inactivation in a hyperpolarizing direction, we speculate that a down-regulation of beta-subunit expression may contribute to the depolarizing shift in the inactivation curve following S.E.
authors.affiliation: Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud Strasse 25, 53105 Bonn, Germany.
authors.forename: R K
authors.initials: RK
authors.lastname: Ellerkmann
authors.forename: S
authors.initials: S
authors.lastname: Remy
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: D
authors.initials: D
authors.lastname: Sochivko
authors.forename: C E
authors.initials: CE
authors.lastname: Elger
authors.forename: B W
authors.initials: BW
authors.lastname: Urban
authors.forename: A
authors.initials: A
authors.lastname: Becker
authors.forename: H
authors.initials: H
authors.lastname: Beck
mesh_terms: D000818:Animals; D018891:Dentate Gyrus / Q000378:metabolism*; D004553:Electric Conductivity; D004558:Electric Stimulation; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D016555:Matched-Pair Analysis; D008564:Membrane Potentials; D018721:Muscarinic Agonists; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D010862:Pilocarpine; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012235:Rhodamines / Q000493:pharmacokinetics; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology*; D016708:Synaptophysin / Q000737:chemistry / Q000235:genetics; D013997:Time Factors
chemical_list: C114557:5-carboxytetramethylrhodamine succinimidyl ester; D005456:Fluorescent Dyes; D018721:Muscarinic Agonists; D021122:Protein Subunits; D012333:RNA, Messenger; D012235:Rhodamines; D015222:Sodium Channels; D016708:Synaptophysin; D010862:Pilocarpine