Molecular Basis of Anticonvulsant Action

Catterall, William

Abstract

Anticonvulsant drugs can be separated into groups based on their clinical efficacy against specific classes of seizures. Data in the literature and preliminary results presented herein suggest that diphenylhydantoin and carbamazepine which are primarily effective against partial and grand mal seizures act selectively on voltage-sensitive sodium channels; phenobarbital, benzodiazepines, and valproic acid which have a broad spectrum of anticonvulsant efficacy act selectively on GABA receptors; and the succinimides and oxazolidinediones which are primarily effective against petit mal seizures do not act on either of these neural substrates. The proposed research will proceed in 3 phases. (1) The binding and action of anticonvulsant drugs at sodium channels and GABA receptors in synaptosomal fractions from mammalian brain will be studied using specific radioligand binding and ion flux assays. Values of KD for drug binding and EC50 for drug action will be derived for representatives of each class of anticonvulsants. Quantitative correlations of these data with therapeutic brain levels of anticonvulsants will be made in rat and monkey brain to rigorously test the hypothesis that some classes of anticonvulsants act selectively at either sodium channels or GABA receptors at pharmacologically relevant concentrations.. (2) For those anticonvulsants which act selectively on sodium channels in mammalian brain the mechanism of drug action will be analyzed in detail using speciffic neurotoxin binding and ion flux assays in synaptosomes. (3) We have recently developed methods to purify protein components of sodium channels from rat brain and to reconstitute sodium channel function from detergent solubilized preparations. We will use these techniques to examine the molecular mechanism of anticonvulsant action on purified sodium channels. Anticonvulsant receptor site() on protein subunit(s) of sodium channels will be identified and characterized. The role of membrane phospholipid in anticonvulsant action will be assessed. These studies will provide a rational basis for the specific pharmacological profiled of anticonvulsant action and will develop the first information on the molecular basis of anticonvulsant action on purified sodium channel preparations.