Late sodium channel openings underlying epileptiform activity are preferentially diminished by the anticonvulsant phenytoin

Abstract

Late openings of sodium channels were observed in outside-out patch recordings from hippocampal neurons in culture. In previous studies of such neurons, a persistent sodium current appeared to underlie the ictal epileptiform activity. All the channel currents were blocked by tetrodotoxin. In addition to the transient openings of sodium channels making up the peak sodium current, there were two types of late channel openings: brief late and burst openings. These late channel openings occurred throughout voltage pulses that lasted 750 ms, producing a persistent sodium current. At -30 mV, this current was 0.4% of the peak current. The late channel openings occurred throughout the physiological range of trans-membrane voltages. The anticonvulsant phenytoin reduced the late channel openings more than the peak currents. The effect on the persistent current was greatest at more depolarized voltages, whereas the effect on peak currents was not substantially voltage dependent. In the presence of 60 microM phenytoin, peak sodium currents at -30 mV were 40-41% of control, as calculated using different methods of analysis. Late currents were 22-24% of control. Phenytoin primarily decreased the number of channel openings, with less effect on the duration of channel openings and no effect on open channel current. This set of findings is consistent with models in which phenytoin binds to the inactivated state of the channel. The preferential effect of phenytoin on the persistent sodium current suggests that an important pharmacological mechanism for a sodium channel anticonvulsant is to reduce late openings of sodium channels, rather than reducing all sodium channel openings. We hypothesize that pharmacological interventions that are most selective in reducing late openings of sodium channels, while leaving early channel openings relatively intact, will be those that produce an anticonvulsant effect while interfering minimally with normal function.