共查询到10条相似文献，搜索用时 125 毫秒
1.
Beta-adrenergic receptor: stereospecific interaction of iodinated beta-blocking agent with high affinity site 总被引：18，自引：0，他引：18
G D Aurbach S A Fedak C J Woodard J S Palmer D Hauser F Troxler 《Science (New York, N.Y.)》1974,186(4170):1223-1224
An iodine-labeled beta-adrenergic inhibitor ((125)l-hydroxybenzylpindolol) binds specifically to a site on turkey erythrocyte membranes. A series of beta-adrenergic agonists and inhibitors compete for this binding site, with apparent affinities paralleling biological effectiveness as activators or inhibitors of catecholaminestimulated adenylate cyclase. The activity of d-(+) agonists or inhibitors was 1 percent (or less) than that of the corresponding l-(-) isomers in competing for binding of the iodinated blocker as well as in affecting catecholamine-stimulated adenylate cyclase. 1-(-)-Norepinephrine was about one-tenth as active as l-(-)-isoproterenol in competing for the beta-blocking agent site. The stereospecificity of the interaction with the iodinated beta-blocking agent and the correspondence between affinity for site and biological potency of analogs suggested that this interaction is involved in function of the beta-adrenergic receptor. 相似文献
2.
Direct demonstration of impaired functionality of a purified desensitized beta-adrenergic receptor in a reconstituted system 总被引：4，自引：0，他引：4
B Strulovici R A Cerione B F Kilpatrick M G Caron R J Lefkowitz 《Science (New York, N.Y.)》1984,225(4664):837-840
Long-term exposure of various cell types to beta-adrenergic agonists such as isoproterenol leads to an attenuated responsiveness ("desensitization") of the adenylate cyclase system to further challenge with these agonists. The turkey erythrocyte model system was used earlier to show that a covalent modification of the receptor (phosphorylation) is associated with this process. The functionality of the "desensitized" beta-adrenergic receptor was assessed by implanting purified beta-adrenergic receptor preparations from control and desensitized turkey erythrocytes into phospholipid mixtures and then fusing them with receptor-deficient cells (Xenopus laevis erythrocytes). Desensitized beta-adrenergic receptors showed a 40 to 50 percent reduction in their ability to couple to the heterologous adenylate cyclase system, comparable to the reduction in their functionality observed in their original membrane environment. These results demonstrate the utility of recently developed receptor reconstitution techniques for assessing the functionality of purified receptors and show a direct link between a covalent modification of a membrane-bound receptor and its impaired functionality in a reconstituted system. 相似文献
3.
The beta-adrenergic agonist isoproterenol and analogs of adenosine 3',5'-monophosphate (cAMP) induced a potassium current, M current, in freshly dissociated gastric smooth muscle cells. Muscarinic agonists suppress this current, apparently by acting at a locus downstream from regulation of cAMP levels by adenylate cyclase and phosphodiesterase. Thus, M current can be induced by an agent and regulated in antagonistic fashion by beta-adrenergic and muscarinic systems. 相似文献
4.
J Black 《Science (New York, N.Y.)》1989,245(4917):486-493
This lecture illustrates the early stages in the planning and discovery of propranolol, an adrenaline beta-adrenergic receptor antagonist, and cimetidine, a histamine H2-receptor antagonist--the first examples of clinically useful drugs from each of these classes. The significance of selective agonists, partial agonists, and syntopic antagonists and the importance of the bioassay and the use of molar models in the drug discovery process are discussed. For the future, an outline of potential developments in hormone-receptor concepts is offered leading to the conclusion that progress may depend on improvements in bioassays and related molar modeling. 相似文献
5.
The signaling pathways by which beta-adrenergic agonists modulate voltage-dependent cardiac sodium currents are unknown, although it is likely that adenosine 3'5'-monophosphate (cAMP) is involved. Single-channel and whole-cell sodium currents were measured in cardiac myocytes and the signal transducing G protein Gs was found to couple beta-adrenergic receptors to sodium channels by both cytoplasmic (indirect) and membrane-delimited (direct) pathways. Hence, Gs can act on at least three effectors in the heart: sodium channels, calcium channels, and adenylyl cyclase. The effect on sodium currents was inhibitory and was enhanced by membrane depolarization. During myocardial ischemia the sodium currents of depolarized cells may be further inhibited by the accompanying increase in catecholamine levels. 相似文献
6.
Molecular characterization of the human beta 3-adrenergic receptor 总被引：67，自引：0，他引：67
L J Emorine S Marullo M M Briend-Sutren G Patey K Tate C Delavier-Klutchko A D Strosberg 《Science (New York, N.Y.)》1989,245(4922):1118-1121
Since the classification of beta-adrenergic receptors (beta-ARs) into beta 1 and beta 2 subtypes, additional beta-ARs have been implicated in the control of various metabolic processes by catecholamines. A human gene has been isolated that encodes a third beta-AR, here referred to as the "beta 3-adrenergic receptor." Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promotes the accumulation of adenosine 3',5'-monophosphate; only 2 of 11 classical beta-AR blockers efficiently inhibited this effect, whereas two others behaved as beta 3-AR agonists. The potency order of beta-AR agonists for the beta 3-AR correlates with their rank order for stimulating various metabolic processes in tissues where atypical adrenergic sites are thought to exist. In particular, novel beta-AR agonists having high thermogenic, antiobesity, and antidiabetic activities in animal models are among the most potent stimulators of the beta 3-AR. 相似文献
7.
Rapid beta-adrenergic modulation of cardiac calcium channel currents by a fast G protein pathway 总被引：14，自引：0，他引：14
beta-Adrenergic agonists activate the G protein, Gs, which stimulates cardiac calcium currents by both cytoplasmic, indirect and membrane-delimited, direct pathways. To test whether beta-adrenergic agonists might use both pathways in the heart, isoproterenol was rapidly applied to cardiac myocytes, resulting in a biphasic increase in cardiac calcium channel currents that had time constants of 150 milliseconds and 36 seconds. beta-Adrenergic antagonists of a G protein inhibitor blocked both the fast and slow responses, whereas the adenylyl cyclase activator forskolin produced only the slow response. The presence of a fast pathway in the heart can explain what the slow pathway cannot account for: the ability of cardiac sympathetic nerves to change heart rate within a single beat. 相似文献
8.
Control of yeast mating signal transduction by a mammalian beta 2-adrenergic receptor and Gs alpha subunit 总被引：6，自引：0，他引：6
K King H G Dohlman J Thorner M G Caron R J Lefkowitz 《Science (New York, N.Y.)》1990,250(4977):121-123
To facilitate functional and mechanistic studies of receptor-G protein interactions, [corrected] the human beta 2-adrenergic receptor (h beta-AR) has been expressed in Saccharomyces cerevisiae. This was achieved by placing a modified h beta-AR gene under control of the galactose-inducible GAL1 promoter. After induction by galactose, functional h beta-AR was expressed at a concentration several hundred times as great as that found in any human tissue. As determined from competitive ligand binding experiments, h beta-AR expressed in yeast displayed characteristic affinities, specificity, and stereoselectivity. Partial activation of the yeast pheromone response pathway by beta-adrenergic receptor agonists was achieved in cells coexpressing h beta-AR and a mammalian G protein (Gs) alpha subunit-demonstrating that these components can couple to each other and to downstream effectors when expressed in yeast. This in vivo reconstitution system provides a new approach for examining ligand binding and G protein coupling to cell surface receptors. 相似文献
9.
M J Lohse J L Benovic J Codina M G Caron R J Lefkowitz 《Science (New York, N.Y.)》1990,248(4962):1547-1550
Homologous or agonist-specific desensitization of beta-adrenergic receptors is thought to be mediated by a specific kinase, the beta-adrenergic receptor kinase (beta ARK). However, recent data suggest that a cofactor is required for this kinase to inhibit receptor function. The complementary DNA for such a cofactor was cloned and found to encode a 418-amino acid protein homologous to the retinal protein arrestin. The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors. 相似文献
10.
beta-Adrenergic regulation of alpha 2-adrenergic receptors in the central nervous system 总被引：1，自引：0，他引：1
Incubation of rat cerebral cortical slices with the beta-adrenergic agonist isoproterenol causes an increase in alpha 2-adrenergic receptor binding in addition to a decrease in beta-adrenergic receptor binding. The effects are rapid and reversible, show a parallel time course, and are blocked by sotalol, a beta-adrenergic receptor antagonist. The beta-mediated regulation of alpha 2-receptor sensitivity at brain norepinephrine synapses may be a mechanism for the homeostatic control of central noradrenergic activity. 相似文献