Phosphorylation of sodium channels mediated by protein kinase-C modulates inhibition by topiramate of tetrodotoxin-sensitive transient sodium current

G. Curia, P. Aracri, E. Colombo, P. Scalmani, M. Mantegazza, G. Avanzini, S. Franceschetti

Research output: Contribution to journalArticle

Abstract

Background and purpose: Topiramate is a novel anticonvulsant known to modulate the activity of several ligand- and voltage-gated ion channels in neurons. The mechanism of action of topiramate, at a molecular level, is still unclear, but the phosphorylation state of the channel/receptor seems to be a factor that is able to influence its activity. We investigated the consequences of phosphorylation of the sodium channel on the effect of topiramate on tetrodotoxin (TTX)-sensitive transient Na + current (I NaT). Experimental approach: I NaT was recorded in dissociated neurons of rat sensorimotor cortex using whole-cell patch-clamp configuration. Key results: We found that topiramate (100 μM) significantly shifted the steady-state I NaT inactivation curve in a hyperpolarized direction. In neurons pre-treated with a PKC-activator, 1-oleoyl-2-acetyl-sn-glycerol (OAG; 2 μM), the net effect of topiramate on steady-state I NaT inactivation was significantly decreased. In addition, OAG also slightly shifted the I NaT activation curve in a hyperpolarized direction, while perfusion with topiramate had no effect on the parameters of I NaT activation. Conclusions and Implications: These data show that PKC-activation can modulate the effect of topiramate on I NaT. This suggests that channel phosphorylation in physiological or pathological conditions (such as epiliepsy), can alter the action of topiramate on sodium currents.

Original languageEnglish
Pages (from-to)792-797
Number of pages6
JournalBritish Journal of Pharmacology
Volume150
Issue number6
DOIs
Publication statusPublished - Mar 18 2007

Keywords

  • Antiepileptic drug
  • PKC
  • Sodium channel
  • Topiramate
  • Transient Na current

ASJC Scopus subject areas

  • Pharmacology

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