Protein-kinase C-dependent Phosphorylation Inhibits the Effect of the Antiepileptic Drug Topiramate on the Persistent Fraction of Sodium Currents

Neuroscience. 2004;127(1):63-8. doi: 10.1016/j.neuroscience.2004.04.040.

Abstract

We investigated the interference of protein-kinase C (PKC)-dependent Na(+) channel phosphorylation on the inhibitory effect that the antiepileptic drug topiramate (TPM) has on persistent Na(+) currents (I(NaP)) by making whole cell patch-clamp and intracellular recordings of rat sensorimotor cortex neurons. The voltage-dependent activation of I(NaP) was significantly shifted in the hyperpolarizing direction when PKC was activated by 1-oleoyl-2-acetyl-sn-glycerol (OAG). TPM reduced the peak amplitude of I(NaP), but it did not counteract the OAG-induced shift in I(NaP) activation. Firing property experiments showed that the firing threshold was lowered by OAG. TPM was unable to counteract this effect, which may be due to OAG-dependent enhancement of the contribution of subthreshold I(NaP). These data suggest that PKC activation may limit the effect of the anticonvulsant TPM on the persistent fraction of Na(+) currents. The channel phosphorylation that may occur in cortical neurons as a result of physiological or pathological (e.g. epileptic) events can modulate the action of TPM on Na(+) currents.

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Anticonvulsants / pharmacology
  • Cell Membrane / drug effects*
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Diglycerides / pharmacology
  • Enzyme Activators / pharmacology
  • Fructose / analogs & derivatives*
  • Fructose / pharmacology*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Patch-Clamp Techniques
  • Phosphorylation / drug effects
  • Protein Kinase C / drug effects
  • Protein Kinase C / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Channels / drug effects*
  • Sodium Channels / metabolism
  • Topiramate

Substances

  • Anticonvulsants
  • Diglycerides
  • Enzyme Activators
  • Sodium Channels
  • Topiramate
  • Fructose
  • 1-oleoyl-2-acetylglycerol
  • Protein Kinase C