The chloride channel is surrounded by a GABA receptor, a nanomolar central benzodiazepine receptor, and a receptor site that binds picrotoxin and related con-vulsants as well as barbiturates and related depressants. This channel and its properties, related to the benzodi-azepines, GABA, and convulsant and barbiturate molecules, have been characterized in detail (26). Picrotoxin binds to the proposed site and modulates benzodiaz-epine and GABA receptor binding in a way that inhibits chloride channel permeability, therefore making the cell more excitable. Barbiturate binding potentiates benzodi-azepine receptor binding and thus indirectly potentiates the GABA effect on opening the chloride channel and enhancing neuronal inhibition. This complex interaction between GABA, benzodiazepines, picrotoxin and related convulsants, and the barbiturates and related depressants is a prime example of how pharmacologic agents modulate the function of ion channels through specific receptor binding.
Benzodiazepines are an important class of compounds that have antianxiety or anxiolytic effects and sedative, muscle relaxant, and anticonvulsant properties (15, 23-25, 27). As anticonvulsants, these compounds are effective in blocking both pentylenetetrazol-induced seizures in animals and, at higher concentrations, maximal electric shock-induced seizures. Benzodiazepines are the most commonly prescribed drugs for the initial treatment of generalized tonic-clonic seizures and status epilepticus in hospital emergency rooms. The anticonvulsant properties of the benzodiazepines, therefore, not only are of academic importance but also have widespread clinical use. The research characterizing this benzodiazepine receptor (16-19, 28, 29) demonstrates AED receptor-mediated regulation of neuronal excitability. Benzodiazepine binding to the nanomolar receptor site potentiates GABA effects on neuronal inhibition, providing one clear mechanism by which these compounds regulate neuronal excitability. Correlative neuropharmacologic studies have indicated that the anxiolytic and anti-pentylenetetrazol-induced anticonvulsant activity of these compounds are mediated through the high-affinity benzodiazepine nanomolar receptors. The effects of benzodiazepines on maximal electric shock-induced seizures and on generalized convulsions, however, cannot be clearly explained by these nanomolar actions.
Stiripentol is a novel antiepileptic compound that is structurally unrelated to any of the other currently marketed antiepileptic drugs (30). Studies in animal models have demonstrated that it produces anticonvulsant effect by increasing GABAergic transmission by enhancing the duration of opening of GABAA receptor channels (31). However, its clinical development was halted because of its inhibitory effect on cytochrome P450 enzymes. Despite this, it has been found to be beneficial for the treatment of early childhood epilepsy, and clinical trials are under way to further characterize its beneficial effect in pediatric patients (30).
Recently two types of GABAA receptor-mediated inhibition have come to the forefront: phasic and tonic. Synaptically released GABA, acting on postsynaptic GABAA receptors, produces "phasic" inhibition, whereas ambient GABA continually present in the extracellular space produces persistent activation of extrasynaptic GABAA receptors, resulting in "tonic" inhibition (32). Elegant studies by Istvan Mody's group strongly indicate that distinct GABAA receptor subtypes mediate these tonic and phasic receptor-mediated inhibitions (32-34). They found that the alpha-4 GABAA receptor subtype were extrasynaptically located and were responsible for tonic inhibition (34). These results suggested that alpha-4/beta/ delta and alpha4/beta/gamma subunit-containing GABAA receptors may be present exclusively extrasynaptically, have a higher affinity for GABA, and not desensitize on the prolonged presence of agonist (35). On the other hand, alpha-1/beta/gamma-2 or alpha-2/beta/gamma-2 receptors are thought to mediate phasic inhibition, since the synaptic currents are known to be sensitive to benzodiaz-epines (36, 37). These studies provide another mechanism for GABAA regulation of synaptic activity.
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