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Vol. 54, Issue 4, 712-721, October 1998
Department of Physiology, National Taiwan University College of
Medicine, and Department of Neurology, National Taiwan University
Hospital, Taiwan, Republic of China
Phenytoin, carbamazepine, and lamotrigine are anticonvulsants
frequently prescribed in seizure clinics. These drugs all show voltage-dependent inhibition of Na+ currents, which has
been implicated as the major mechanism underlying the antiepileptic
effect. In this study, I examine the inhibition of Na+
currents by mixtures of different anticonvulsants. Quantitative analysis of the shift of steady state inactivation curve in the presence of multiple drugs argues that one channel can be occupied by
only one drug molecule. Moreover, the recovery from inhibition by a
mixture of two drugs (a fast-unbinding drug plus a slow-unbinding drug)
is faster, or at least not slower, than the recovery from inhibition by
the slow-unbinding drug alone. Such kinetic characteristics further
strengthen the argument that binding of one anticonvulsant to the
Na+ channel precludes binding of the other. It also is
found that these anticonvulsants are effective inhibitors of
Na+ currents only when applied externally, not internally.
Altogether these findings suggest that phenytoin, carbamazepine, and
lamotrigine bind to a common receptor located on the extracellular side
of the Na+ channel. Because these anticonvulsants all have
much higher affinity to the inactivated state than to the resting state
of the Na+ channel, the anticonvulsant receptor probably
does not exist in the resting state. Thus, there may be correlative
conformational changes for the making of the receptor on the
extracellular side of the channel during the gating process.
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