INHIBITION AND STIMULATION OF ADENYLYL CYCLASE BY 5-HT RECEPTORS IN GUINEA PIG AND RAT HIPPOCAMPAL MEMBRANES: CLASSIFICATION OF THE RECEPTORS AND GTP-BINDING PROTEINS MEDIATING THE RESPONSES.
Item
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Title
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INHIBITION AND STIMULATION OF ADENYLYL CYCLASE BY 5-HT RECEPTORS IN GUINEA PIG AND RAT HIPPOCAMPAL MEMBRANES: CLASSIFICATION OF THE RECEPTORS AND GTP-BINDING PROTEINS MEDIATING THE RESPONSES.
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Identifier
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AAI8801701
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identifier
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8801701
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Creator
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DE VIVO, MICHAEL.
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Contributor
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Saul Maayani
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Date
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1987
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Language
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English
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Publisher
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City University of New York.
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Subject
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Health Sciences, Pharmacology
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Abstract
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In guinea pig hippocampal membranes, 5-HT has a net stimulatory or inhibitory effect on adenylyl cyclase (AC) activity depending upon the degree of activation of the cyclase by forskolin. In the absence of forskolin, or in the presence of low concentrations of forskolin, 5-HT stimulates AC activity, whereas in the presence of high (micromolar) concentrations of forskolin, 5-HT inhibits AC activity.;Inhibition of AC by 5-HT is saturable and follows simple Michaelis-Menten kinetics. Antagonists competitively shift the concentration-response curve to 5-HT to the right with no reduction in the maximal percentage of inhibition. These data suggest that inhibition is mediated by a single population of receptors. Pharmacological classification of the inhibition demonstrates that the effect is mediated by a receptor homologous with the 5-HT{dollar}\sb{lcub}\rm 1A{rcub}{dollar} binding site. 5-HT{dollar}\sb{lcub}\rm 1A{rcub}{dollar} receptor-mediated inhibition of AC is also measurable in membranes from rat cerebral cortex and hippocampus.;Stimulation of AC activity by 5-HT is mediated by two distinct populations of receptors, one population that is classified as 5-HT{dollar}\sb{lcub}\rm 1A{rcub}{dollar}, another that is designated as R{dollar}\sb{lcub}\rm L{rcub}{dollar} (Shenker et al., 1985). Reducing the membrane concentration in the assay results in a reduction of the contribution of the 5-HT{dollar}\sb{lcub}\rm 1A{rcub}{dollar} receptor to the stimulation, permitting pharmacological analysis of the R{dollar}\sb{lcub}\rm L{rcub}{dollar}-mediated response. Based on the affinities of the antagonists spiperone, fluphenazine and mianserin, the stimulation is mediated by a receptor homologous with the receptor that stimulates AC in infant rat collicular membranes (Nelson et al., 1980a,b).;Inhibition of adenylyl cyclase activity by 5-HT{dollar}\sb{lcub}\rm 1A{rcub}{dollar} receptor-stimulation requires micromolar concentrations of GTP and Mg{dollar}\sp{lcub}++{rcub}{dollar}. In vivo administration of pertussis toxin abolishes the 5-HT-mediated inhibition of adenylyl cyclase activity in membranes. These data indicate that the inhibitory effect is mediated by a GTP-binding protein, presumably G{dollar}\sb{lcub}\rm i{rcub}{dollar}. Stimulation of adenylyl cyclase activity requires GTP and millimolar concentrations of Mg{dollar}\sp{lcub}++{rcub}{dollar}. 5-HT receptor-stimulation results in a reduction in the EC{dollar}\sb{lcub}50{rcub}{dollar} value for M{dollar}\sp{lcub}++{rcub}{dollar} in stimulating adenylyl cyclase, a characteristic of G{dollar}\sb{lcub}\rm s{rcub}{dollar} proteins (Iyengar and Birnbaumer, 1982).
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
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Program
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Biomedical Sciences
