• MAP kinase;
  • patch clamp;
  • protein kinase C;
  • rat


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.