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.
Curia, G., Aracri, P., Sancini, G., Mantegazza, M., Avanzini, G., Franceschetti, S. (2004). Protein-kinase C-dependent phosphorylation inhibits the effect of the antiepileptic drug topiramate on the persistent fraction of sodium currents. NEUROSCIENCE, 127(1), 63-68 [10.1016/j.neuroscience.2004.04.040].
Protein-kinase C-dependent phosphorylation inhibits the effect of the antiepileptic drug topiramate on the persistent fraction of sodium currents
ARACRI, PATRIZIA;SANCINI, GIULIO ALFREDO;
2004
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.
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