Over the past few years, some major differences between the interaction of agonists and antagonists with the beta-adrenoreceptor have been observed. Agonist binding shows 2 affinity states (high and low) which are determined by the receptor-guanine nucleotide binding protein (N-site) interaction, whereas, antagonist binding shows only a single class of binding sites. The long term objective of the proposed research is to characterize, after irreversible blockade, the process of receptor regeneration, to correlate agonist binding states with biochemical responses and to determine possible cellular components that regulate receptor-N-site interactions. After irreversible blockade of the beta-adrenoreceptor, the time course of recovery will be determined in rat C6-glioma cells with respect to: antagonist binding sites, agonist binding states, cellular localization, receptor down regulation and the stimulation of adenylate cyclase, and phospholipid methylation. The lag period between the recovery of antagonist and agonist high affinity binding sites will be characterized by receptor photoaffinity labeling and attempts will be made to alter the lag period with inhibitors of microtubles, protein synthesis, glycosylation and ATP synthesis. Using whole animals, the regulation of the recovery in the heart and lung antagonist and agonist binding sites, adenylate cyclase stimulation and the lag period between the recovery of antagonist and agonist sites will be determined during hypo- and hyperthyroidism and after treatment with glucocorticoids and 6-hydroxydopamine. The proposed studies will provide basic information on the cellular processing of beta-adrenoreceptors. This information may indicate areas where lesions may occur, resulting in altered receptor coupling and receptor mediated physiological responses associated with disease or drug treatment.
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