Richard W. Olsen

The GABA postsynaptic membrane receptor-ionophore complex

The function of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), has been implicated in the mode of action of many drugs which excite or depress the central nervous system. Many convulsant agents appear to block GABA action whereas anticonvulsants enhance GABA action. Some of these drug effects involve altered G AB A-mediated synaptic transmission at the level of GABA biosynthesis, release from nerve endings, uptake into cells, and metabolic degradation. A greater number of agents of diverse classes appear to affect GABA action at the postsynaptic membrane, as determined from both electrophysiological and biochemical studies. The recently developed in vitro radioactive receptor binding assays have led to a wealth of new information about GABA action and its alteration by drugs. GABA inhibitory transmission involves the regulation, by GABA binding to its receptor site, of chloride ion channels. In this GABA receptor-ionophore system, other drug receptor sites, one for benzodiazepines and one for barbiturates/picrotoxinin (and related agents) appear to form a multicomponent complex. In this complex, the drugs binding to any of the three receptor categories are visualized to have an effect on GABA-associated chloride channel regulation. Available evidence suggests that the complex mediates many of the actions of numerous excitatory and depressant drugs showing a variety of pharmacological effects.

The GABA Receptor-Chloride Ion Channel Protein Complex

The majority of inhibitory synaptic transmission in the central nervous system involves γ-aminobutyric acid (GABA) as the neurotransmitter (1). The signal transduction mechanism at the majority of GABA synapses involves a ligand-gated chloride channel; binding of GABA to its receptor increases postsynaptic membrane chloride conductance and inhibits the target cell (2). This GABA receptor, called GABAA, is defined pharmacologically by sensitivity to the agonist muscimol ana the antagonist bicuculline (3). At least one other type of GABA receptor exists, GABAB, defined as insensitive to bicuculline and sensitive to baclofen; GKBAB receptors are coupled to GTP-binding proteins for a variety of signal transduction mechanisms (4). GABAA receptor function is also modulated by at least three classes of centrally active drugs, the picrotoxin-like convulsants, that inhibit GABA function, and the benzodiazepines and the barbiturates, both of which enhance GABA function (5).

GABA-drug interactions

γ-Aminobutyric acid is the major inhibitory neurotransmitter in the central nervous system and is widely utilized in virtually all anatomic regions of the brain and spinal cord [1,2]. In recent years, pharmacological evidence at all levels (organismal, tissue, cellular, and molecular) have implicated GABA in a variety of human clinical problems and, correspondingly, in the action of numerous drugs showing general excitatory or depressant action on the central nervous system [3–5]. These include convulsants like picrotoxin [6], bicuculline [7], cage convulsants [8], pentylenetetrazol [9], and convulsant benzodiazepines [10, 11], as well as depressants like benzodiazepines (used for anxiolytic, anticonvulsant, sedative-hypnotic, or muscle relaxant activity [12], barbiturates (used today as anticonvulsants and general anesthetics, and formerly as sedative-hypnotics [13]), other general anesthetics [14, 15], including ethanol [16, 17], and a variety of related substances [18]. Because of the widespread function of GABA in the brain, interactions with virtually all neuropharmacological agents and other neurotransmitters have been described. However, increasing bodies of evidence suggest that the drugs mentioned above act by modifying the postsynaptic response to GABA directly at the GABA receptor-chloride ion channel complex [19,20].

Structural, Developmental and Functional Heterogeneity of Rat GABAA Receptors

My laboratory has had a long interest in multigene families, starting with our earlier work on the developmental regulation of hemoglobin switching. I have especially been impressed both by the number of multigene families in the vertebrate genome and by their widespread developmental regulation, as exemplified by switching within the globin gene families. Even the lamprey, whose adult hemoglobin, unlike those of higher vertebrates, contains only one type of globin chain, has different forms in its larval and adult stages.

GABAA -Benzodiazepine Receptors: Demonstration of Pharmacological Subtypes in the Brain

The GABAA receptor is a ligand-gated chloride ion channel that mediates the majority of rapid-acting inhibitory synapses in the central nervous system (Olsen and Venter, 1986). The GABAA receptors are also the target of numerous clinically important depressant and excitatory drugs (Olsen, 1981; Tallman and Gallager, 1985; Biggio and Costa, 1988). The convulsant drug bicuculline acts as a competitive antagonist at the GABA recognition site, beta-carbolines block GABA function as ’ inverse agonists’ at the benzodiazepine recognition site, and picrotoxin and cage convulsants inhibit the chloride channel function at a site on the receptor complex distinct from the GABA and benzodiazepine receptor sites. Clinically important depressant benzodiazepines enhance GABA-mediated inhibition via their own binding sites on the receptor complex. Still additional sites on the receptor-ion channel complex mediate the action of barbiturates, steroid anesthetics, and possibly ethanol to enhance GABAA receptor function at the membrane level (Olsen and Venter, 1986; Biggio and Costa, 1988).

Soluble GABA/Benzodiazepine/Barbiturate Receptor Interactions in Mammalian Brain

GABA (γ-aminobutyric acid) is now established as the major neurotransmitter in mammalian brain, and mediates its effects via the GABA receptor and an associated chloride ion channel (1]. Further accumulated evidence suggests that some GABA receptors possess modulatory sites for certain centrally active compounds, the benzodiazepines and the barbiturates [1].