Late sodium channel openings underlying epileptiform activity are
preferentially diminished by the anticonvulsant phenytoin.
Michael M. Segal and Andrea F. Douglas.
Dept. of Neurology, Children's Hospital, and 2Program in Neuroscience,
Harvard Medical School, Boston MA 02115 USA.
APStracts 4:0059N, 1997.
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
(Segal 1994). 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, while the effect on peak currents was not substantially
voltage dependent. In the presence of 60 æM 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.
Received 18 October 1996; accepted in final form 4 February 1997.
APS Manuscript Number J700-5.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 20 February 1997