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.
Curia
G
G
Department of Neurophysiology, Laboratory of Experimental Epileptology, C. Besta National Neurological Institute, Via Celoria 11, 20133 Milan, Italy.
Aracri
P
P
Sancini
G
G
Mantegazza
M
M
Avanzini
G
G
Franceschetti
S
S
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D000077236:Topiramate
D000927:Anticonvulsants; D004075:Diglycerides; D020536:Enzyme Activators; D015222:Sodium Channels; D000077236:Topiramate; D005632:Fructose; C038237:1-oleoyl-2-acetylglycerol; D011493:Protein Kinase C