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. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.