Protein-kinase C-dependent phosphorylation inhibits the effect of the antiepileptic drug topiramate on the persistent fraction of sodium currents

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.