Phe310 in transmembrane VI of the alpha1B-adrenergic receptor is a key switch residue involved in activation and catecholamine ring aromatic bonding. (1/16)

Pharmacophore mapping of adrenergic receptors indicates that the phenyl ring of catecholamine agonists is involved in receptor binding and activation. Here we evaluated Phe310, Phe311, and Phe303 in transmembrane VI (TMVI), as well as Tyr348 in TMVII of the alpha1B-adrenergic receptor (alpha1B-AR), which have been implicated in a catechol-ring interaction. Neither catecholamine docking studies nor mutagenesis studies of Phe311, Phe303, or Tyr348 supported a role for these residues in catechol-ring binding. By contrast, docking studies indicated that the Phe310 side chain is well positioned to interact with the catechol-ring, and substituted cysteine accessibility method studies revealed that the side chain of the 310, but not 311 residue, is both solvent accessible and directed into the agonist-binding pocket. Also, saturation mutagenesis of both Phe310 and Phe311 revealed for the former, but not for the latter, a direct relationship between side chain volume and agonist affinity, and that aromaticity is essential for wild-type agonist binding, and for both wild-type agonist potency and efficacy. Moreover, studies of Phe310 mutants combined with a previously described constitutively active alpha1B-AR mutant, A293E, indicated that although not required for spontaneous receptor isomerization from the basal state, R, to a partially activated conformation R', interaction of Phe310 with catecholamine agonists is essential for isomerization from R' to the fully activated state, R.  (+info)

Modulation in vivo of beta-adrenergic-receptor subtypes in rat brown adipose tissue by the thermogenic agonist Ro 16-8714. (2/16)

The number of beta 3-adrenergic receptors (AR) in plasma membranes from interscapular brown adipose tissue (IBAT) was decreased by 62% in lean Zucker rats treated with the thermogenic beta-adrenergic agonist Ro 16-8714 as compared with controls after 72 h of treatment. The loss of beta 3-AR number was preceded by a 93% decrease in the steady-state level of beta 3-AR mRNA at 30 h. Similar results were obtained in obese (fa/fa) Zucker rats. Ro 16-8714 had no effect on the number of beta 1- and beta 2-ARs in IBAT. This is the first report to demonstrate that the beta 3-AR in IBAT can be specifically down-regulated in vivo by exposure to a thermogenic agonist.  (+info)

The drug LY79771 affects fat regain by starved and refed BHE rats. (3/16)

The effect of the drug LY79771 on the fat rebound response of BHE rats to starvation-refeeding was studied. Three experiments were conducted. Experiment 1 determined the effect of the drug on the composition of the regained weight following a period of starvation. The drug-treated rats had significantly less body fat after refeeding than did the control rats. Experiment 2 measured the liver and fat pad lipid levels and the activities of two NADP-linked enzymes after starvation-refeeding. The classic two- to threefold hepatic glucose-6-phosphate dehydrogenase and malic enzyme overshoot and increase in liver and fat pad lipid levels were seen in refed controls but not in refed LY79771-treated rats. Experiment 3 measured de novo fatty acid synthesis in LY79771-treated and control rats. Treatment with LY79771 resulted in lower hepatic fatty acid synthesis in starved and refed rats. These observations suggest that LY79771 can be effective in preventing fat regain following energy deprivation.  (+info)

Expression of neuropeptide hormone receptors in human adrenal tumors and cell lines: antiproliferative effects of peptide analogues. (4/16)

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Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors. (5/16)

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Role of peripheral versus spinal 5-HT(7) receptors in the modulation of pain undersensitizing conditions. (6/16)

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Anti-tumor effects of peptide analogs targeting neuropeptide hormone receptors on mouse pheochromocytoma cells. (7/16)

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The novel thermogenic beta-adrenergic agonist Ro 16-8714 increases the interscapular brown-fat beta-receptor-adenylate cyclase and the uncoupling-protein mRNA level in obese (fa/fa) Zucker rats. (8/16)

In obese (fa/fa) rats both the total (-)-isoprenaline- and NaF-stimulated adenylate cyclase activities of interscapular brown-adipose-tissue (IBAT) plasma membranes were decreased as compared with lean rats by 40 and 38% respectively. An acute treatment with Ro 16-8714 increased (-)-isoprenaline- and NaF-stimulated adenylate cyclase activities by 2.5- and 2.0-fold respectively, and beta-adrenoceptor number 2.8-fold in obese rat IBAT, but it had no effect on these parameters in lean rats. It increased mRNA for mitochondrial uncoupling protein in both lean and obese rats to the same extent.  (+info)

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