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: R K Ellerkmann, S Remy, J Chen, D Sochivko, C E Elger, B W Urban, A Becker, H Beck
• Journal: Neuroscience (Neuroscience) Vol. 119 Issue 2 Pg. 323-33 ( 2003) ISSN: 0306-4522 [Print] United States
• PMID: 12770549 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-carboxytetramethylrhodamine succinimidyl ester
• Fluorescent Dyes
• Muscarinic Agonists
• Protein Subunits
• RNA, Messenger
• Rhodamines
• Sodium Channels
• Synaptophysin
• Pilocarpine

Topics

• Animals
• Dentate Gyrus (metabolism)
• Electric Conductivity
• Electric Stimulation
• Fluorescent Dyes (pharmacokinetics)
• Gene Expression Regulation (drug effects)
• In Vitro Techniques
• Male
• Matched-Pair Analysis
• Membrane Potentials
• Muscarinic Agonists
• Neurons (physiology)
• Patch-Clamp Techniques (methods)
• Pilocarpine
• Protein Subunits (chemistry, genetics)
• RNA, Messenger (biosynthesis)
• Rats
• Rats, Wistar
• Reverse Transcriptase Polymerase Chain Reaction (methods)
• Rhodamines (pharmacokinetics)
• Sodium Channels (genetics, physiology)
• Status Epilepticus (chemically induced, pathology)
• Synaptophysin (chemistry, genetics)
• Time Factors