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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM034905-01
Application #
3286748
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1985-05-01
Project End
1988-04-30
Budget Start
1985-05-01
Budget End
1986-04-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Kuchin, Sergei; Vyas, Valmik K; Carlson, Marian (2002) Snf1 protein kinase and the repressors Nrg1 and Nrg2 regulate FLO11, haploid invasive growth, and diploid pseudohyphal differentiation. Mol Cell Biol 22:3994-4000
Bolden, C P; Baker, S P (1990) Effect of acetylethylcholine mustard on muscarinic receptor-coupled attenuation of cAMP formation in intact GH3 cells. J Pharmacol Exp Ther 254:136-41
Standifer, K M; Pitha, J; Baker, S P (1989) Carbostyril-based beta-adrenergic agonists: evidence for long lasting or apparent irreversible receptor binding and activation of adenylate cyclase activity in vitro. Naunyn Schmiedebergs Arch Pharmacol 339:129-37
Baker, S P; Buss, D D; Epstein, M L et al. (1989) Effect of chronic hypoxia on cardiac beta-adrenergic and muscarinic receptors during maturation. Res Commun Chem Pathol Pharmacol 63:307-15
Baker, S P; Standifer, K M; Kalberg, C J et al. (1988) Irreversible binding and recovery of the norepinephrine uptake system using an alkylating derivative of norepinephrine. J Neurochem 50:1044-52
Meyer, E M; Otero, D H; Morgan, E et al. (1987) Effects of acetylethylcholine mustard on [3H]quinuclidinyl benzilate binding and acetylcholine release in rat brain synaptosomes. J Neurochem 48:477-82
Baker, S P; Henneman, W W; Carpentier, R G et al. (1987) Depressed atrial inotropic response in the rat with chronic ethanol ingestion. Alcohol 4:7-10
Nelson, C A; Muther, T F; Pitha, J et al. (1986) Differential recovery of beta adrenoreceptor antagonist and agonist high affinity binding sites in the guinea-pig lung after irreversible blockade. J Pharmacol Exp Ther 237:830-6
Baker, S P; Posner, P (1986) Irreversible binding of acetylethylcholine mustard to cardiac cholinergic muscarinic receptors. Mol Pharmacol 30:411-8
Baker, S P; Sumners, C; Pitha, J et al. (1986) Characteristics of the beta-adrenoreceptor from neuronal and glial cells in primary cultures of rat brain. J Neurochem 47:1318-26

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