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


METHODS
I(NaT) was recorded in dissociated neurons of rat sensorimotor cortex using whole-cell patch-clamp configuration.


RESULTS
We found that topiramate (100 microM) 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 microM), 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
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.
Curia
G
G
Department of Neurophysiology, Laboratory of Experimental Epileptology, C Besta National Neurological Institute, Milano, Italy. giulia.curia@mcgill.ca
Aracri
P
P
Colombo
E
E
Scalmani
P
P
Mantegazza
M
M
Avanzini
G
G
Franceschetti
S
S
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009044:Motor Cortex / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism*; D013779:Tetrodotoxin / Q000633:toxicity; D000077236:Topiramate
D000927:Anticonvulsants; D004075:Diglycerides; D015222:Sodium Channels; D000077236:Topiramate; D005632:Fructose; D013779:Tetrodotoxin; C038237:1-oleoyl-2-acetylglycerol; D011493:Protein Kinase C