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

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.