Gamma aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. The binding of GABA to postsynaptic GABA receptors opens a chloride-selective ion pore that is an integral component of the multimeric receptor complex. The resulting chloride flux across the cell membrane inhibits the postsynaptic neuron. Dysfunctions in GABA-mediated inhibition have been implicated in the etiology of a variety of neurological and psychological disorders. Furthermore, GABA receptors are a primary target for several neuroactive drugs including barbiturates, steroids, general anesthetics, and benzodiazepines (BZ); the latter of which is the subject of this proposal. Although it has been known for quite some time that BZs modulate GABA receptors, the molecular mechanism is still unresolved. This proposal will use a combination of molecular biology, electrophysiology, single oocyte radioactive ligand binding, and site directed fluorescent labeling to gain structural and functional insights into the actions of BZs on GABA receptors. Some of these techniques are new to the BZ field and it is hoped they will bring some fresh perspectives to the problem. ? The design of more efficacious BZs that can target the many different GABA receptor subtypes that have been identified in the brain will ultimately depend on understanding the structural requirements and precise mechanism of action of this important class of neuroactive compounds. The results from these proposed studies are expected to contribute to that effort. ? ?
