Kinase-dependent loss of Na+ channel slow-inactivation in rat CA1 hippocampal pyramidal cell dendrites after brief exposure to convulsants.
Na+ channels in the dendrites of rat CA1 pyramidal neurons display a profound activity-dependent inactivation, termed slow inactivation, that limits excitability in the dendrites even at low physiological rates of firing. The magnitude of this slow inactivation is powerfully modulated by a protein kinase C-dependent process. Because activation of kinases is a rapid and common feature of a number of seizure models, we hypothesized that a loss of slow inactivation of Na+ channels might exacerbate other changes in excitability. Thus, we observed the effects of a brief (5 min) chemical convulsant treatment on Na+ currents and action potentials in hippocampal slices. We found that slow inactivation decreased significantly and remained decreased for at least 30 min after return to control conditions. Pretreatment with either chelerythrine, a protein kinase C inhibitor, or U0126, a mitogen-activated protein kinase/extracellular signal regulated kinase kinase (MEK) inhibitor, blocked this reduction of slow inactivation. These results demonstrate that a brief period of hyperexcitability leads to a rapid, protein kinase-dependent loss of slow inactivation of Na+ channels that would contribute to and perhaps prolong the hyperexcitable state.
Loftis
Jordan L
JL
Department of Biology and Biochemistry, University of Houston, 4800 Calhoun Road, Houston, TX 77204-5513, USA.
King
Diana D
DD
Colbert
Costa M
CM
D000200:Action Potentials / Q000187:drug effects; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D002070:Butadienes / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology*; D003712:Dendrites / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010617:Phenanthridines / Q000494:pharmacology; D010770:Phosphotransferases / Q000378:metabolism*; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000502:physiology*; D013997:Time Factors
D000470:Alkaloids; D053119:Benzophenanthridines; D002070:Butadienes; D003292:Convulsants; D004791:Enzyme Inhibitors; D009570:Nitriles; D010617:Phenanthridines; D015222:Sodium Channels; C113580:U 0126; C016299:chelerythrine; D010770:Phosphotransferases