REGULATION AND TURNOVER OF THE BENZODIAZEPINE RECEPTOR

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The goal of this research is to gain an understanding, on a molecular level, of the control mechanisms and/or chemical signals that regulate receptor number, affinity and distribution in neuronal cells. In particular, we wish to determine how mechanisms for control of receptor number and distribution in neurons compare to those in non-neural cells. While much is known of receptor turnover (synthesis and degradation) in non-neural cells, there have been, to the best of our knowledge, no thorough studies of the synthesis and degradation of a receptor localized to the central nervous system. Much of the work that has appeared has focused upon 'down-regulation' or 'up-regulation' of receptor numbers; however, the kinetics of such changes provide only limited information about cellular mechanisms of receptor synthesis and degradation. Receptor regulation may be investigated more meaningfully if the fate of the receptor is followed directly with a specific probe that does not alter the rates of receptor turnover. We have shown that the chemosensitivity of neurons in culture to gamma-aminobutyric acid is potentiated by benzodiazepines which are minor tranquilizers, anticonvulsants and skeletal muscle relaxants that probably act by enhancing inhibitory neuronal activity in the CNS. The results of combined binding and electrophysiological experiments are consistent with the presence of a functional high affinity benzodiazepine receptor that can be specifically and irreversibly labeled with flunitrazepam as a photoaffinity ligand. Initial experiments suggest that benzodiazepine receptor turnover can be investigated with this probe. These studies will be extended under the current proposal. The principal objectives of this proposal are 1) to investigate the relationship of the biosynthetic and degradative steps to the maintenance of receptor number, and 2) o determine the effects of acute and long term exposure of receptor to ligands on receptor number and/or affinity, using cell cultures derived from embryonic chick brain and spinal cord.