REGULATION AND TURNOVER OF THE BENZODIAZEPINE RECEPTOR

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The long-term goal of our research is to understand, on a molecular level, the control mechanisms that dynamically regulate neurotransmitter receptor distribution and function. The gamma-aminobutyric acid-A receptor (GABA-A-R) is of particular interest in this respect, both because it is one of the most widely distributed neurotransmitter receptors in the nervous system, and because it is a target for three important families of drugs-the benzodiazepines, the barbiturates, and the steroids-which bind to distinct modulatory sites on the GABA-A-R. Remarkably, the interaction of these modulators with the GABA-A-R is itself subject to regulation in response to chronic exposure to these and other drugs, including the transmitter, GABA. The goals of this proposal are to investigate mechanisms of GABA-A-R regulation in a primary monolayer cell culture system. Toward this end, the methods of radioligand binding, molecular biology, 36-Cl uptake, and electrophysiology will be employed to investigate the causes, mechanisms, and consequences of GABA-A-R regulation. In particular, we will define the pharmacology of GABA-A-R regulation by steroids, and will relate changes in GABA-A-R subunit gene expression to functional and ligand-binding properties of the receptor.