Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The beta 2-adrenergic receptor undergoes isomerization between an inactive conformation (R) and an active conformation (R*). The formation of the active conformation of the receptor molecule can be promoted by adrenergic agonists or by mutations in the third cytoplasmic domain that constitutively activate the receptor. Here we show that, of several beta-adrenergic receptor-blocking drugs tested, only two, ICI 118551 and betaxolol, inhibit the basal signaling activity of the beta 2-adrenergic receptor, thus acting as negative antagonists. We document the molecular properties of the more efficacious ICI 118551; (i) it shows higher affinity for the inactive form of the receptor and (ii) it inhibits the spontaneous formation of a beta-adrenergic receptor kinase substrate by the receptor. These properties are opposite those of adrenergic agonists, indicating that, in a fashion reciprocal to that of agonists, negative antagonists promote the formation of an inactive conformation of the receptor.
Mol Pharmacol 1994 Mar
PMID:Negative antagonists promote an inactive conformation of the beta 2-adrenergic receptor. 790 4

The density and distribution of beta 1- and beta 2-adrenoceptors in the atrioventricular conducting system and interatrial and interventricular septa from human hearts with idiopathic dilated cardiomyopathy and ischemic heart disease was determined by quantitative autoradiography using (-)[125I]cyanopindolol and the selective beta 1-adrenoceptor antagonist CGP 20712A and the selective beta 2-adrenoceptor antagonist ICI 118,551. Both beta 1- and beta 2-adrenoceptors were present in the atrioventricular node, bundle of His, interatrial and interventricular septa. No differences in the density or proportions of beta 1- and beta 2-adrenoceptors in the atrioventricular node, bundle of His, interatrial septum and interventricular septum were observed between hearts with idiopathic dilated cardiomyopathy or ischemic heart disease (P > 0.05) so further analysis did not distinguish between the two aetiologies. The density of beta 1-adrenoceptors was lower in the bundle of His (5.0 +/- 1.7 fmol/mg protein) than in the atrioventricular node (22.2 +/- 5.7 fmol/mg protein, P < 0.05), the interatrial septum (29.6 +/- 4.5 fmol/mg protein, P < 0.001) and interventricular septum (24.9 +/- 5.2 fmol/mg protein, P < 0.005, n = 8 for all values). The atrioventricular node, interatrial and interventricular septa had similar densities of beta 1-adrenoceptors (P = 0.60, ANOVA). The distribution of beta 2-adrenoceptors in the atrioventricular node (21.5 +/- 4.1 fmol/mg protein), bundle of His (12.9 +/- 2.6 fmol/mg protein) and atrial (16.7 +/- 2.3 fmol/mg protein) and septal myocardium (13.8 +/- 2.5 fmol/mg protein, n = 8 for all values) was uniform (P = 0.18, ANOVA). The percentage of beta 1- and beta 2-adrenoceptors in the atrioventricular node, bundle of His, interatrial and interventricular septa was uneven (P < 0.001, ANOVA). There was a higher proportion of beta 2-adrenoceptors in the bundle of His (72 +/- 6%) than in the atrioventricular node (51 +/- 3%, P < 0.01), interatrial septum (36 +/- 1%, P < 0.001) and interventricular septum (36 +/- 1%, P < 0.001).
J Mol Cell Cardiol 1994 Mar
PMID:Autoradiographic localization and quantitation of beta 1- and beta 2-adrenoceptors in the human atrioventricular conducting system: a comparison of patients with idiopathic dilated cardiomyopathy and ischemic heart disease. 791 35

Stimulation of adenylyl cyclase mediates the effects of beta-adrenergic agonists and prostaglandin E2 (PGE2) on tracheobronchial epithelial cell function by increasing intracellular cyclic adenosine monophosphate (cAMP). In turn, increases in cAMP affect airway function by modulating ciliary beating, chloride and water transport, mucus secretion, and release of bronchoactive substances. This study examined the function and regulation of the beta-adrenergic receptor-adenylyl cyclase system (beta AR-AC) in tracheal epithelial cells isolated from the rabbit, a frequently used animal model of airway reactivity, inflammation, and electrolyte transport. beta AR number, assessed by ligand binding using the non-subtype-specific beta-antagonist [125I]iodopindolol, averaged approximately 10,700 beta AR/cell (400 fmol/mg membrane protein). Greater than 85% of the receptors were of the beta 2 subtype as determined by competitive antagonist displacement of iodopindolol by selective beta 1- (betaxolol) and beta 2- (ICI 118,551) antagonists. cAMP synthesis was stimulated with isoproterenol, PGE2, and forskolin in a time- and concentration-dependent fashion. Preincubation of epithelial cells for 30 min with either isoproterenol (10 microM) or the peptide inflammatory mediator, bradykinin (100 microM), markedly depressed subsequent isoproterenol-stimulated cAMP synthesis. Isoproterenol-induced beta AR-AC desensitization appeared to be homologous since cAMP responses to PGE2 and forskolin, a direct activator of adenylyl cyclase, were not reduced. The effect of bradykinin on isoproterenol-stimulated cAMP response was mimicked by preincubation with either dioctanoyl glyceride or phorbol myristate acetate, activators of protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1994 Sep
PMID:Functional behavior of the beta-adrenergic receptor-adenylyl cyclase system in rabbit airway epithelium. 791 96

The GH3 pituitary cell line has been used to investigate the role of the oestrogen receptor (ER) as a modulator of mitogenic signals in tumour cells in the absence of exogenous oestrogen. Using a chemically defined, serum- and oestrogen-free medium, we have demonstrated that the pure steroidal anti-oestrogens ICI 182780 and ICI 164384 are capable of blocking growth by more than 50% after 5 days of culture. Studies with conditioned medium have indicated that the basal growth is due to the secretion of autocrine growth stimulatory substances. Under serum- and oestrogen-free conditions, insulin and IGF-I increased the growth rate of these cells by twofold over a 5-day treatment period, and this effect was also blocked by the anti-oestrogens ICI 182780 and ICI 164384 (50% of maximum inhibition at 0.6 and 6 nM respectively). To explore the potential mechanism by which the ER apparently facilitates the growth factor effects under oestrogen-free conditions, GH3 cells were transiently transfected with a plasmid reporter containing the vitellogenin oestrogen response element (delta MTV-ERE-LUC). We have shown that as well as oestradiol (OE2), insulin and IGF-I induce luciferase activity by between two- and sevenfold (four experiments), and these effects were completely blocked by ICI 182780. In contrast, growth factors and OE2 were unable to induce luciferase expression when transfections were performed with a plasmid reporter lacking the oestrogen response element. The studies presented here strongly suggest that, in the absence of oestrogen, the ER in these pituitary tumour cells has a role in growth, as peptide factors are able to induce its conversion to a state which is capable of up-regulating the transcription of key growth-promoting genes.
J Mol Endocrinol 1994 Jun
PMID:The oestrogen receptor modulates growth of pituitary tumour cells in the absence of exogenous oestrogen. 791 69

The estrogen receptor (ER) typically activates gene transcription by binding to estrogen-responsive elements (EREs). The brain creatine kinase (BCK) promoter is responsive to estrogen but contains no ERE-related sequence. To investigate the mechanism of estrogen induction, we have introduced the estrogen receptor into HeLa cells and primary rat cardiomyocytes and fibroblasts along with 195 bp of BCK promoter linked to a chloramphenicol acetyltransferase (CAT) reporter gene. A 10-fold stimulation of CAT activity was observed in the presence of beta-estradiol in both HeLa and rat primary fibroblasts, but no induction was observed in primary rat cardiomyocytes. In contrast, a control vitellogenin gene construct which contains a typical ERE was induced in an ER-dependent manner in all cell types studied. Estrogen induction in HeLa was not sensitive to cycloheximide and was blocked by the ER antagonists tamoxifen and ICI 164,384. Analysis of 5' deletion and linker-scanning mutations indicates sequences between bp -45 and -75 including a TA-rich sequence and a CCAAT sequence to be crucial for stimulation of the BCK promoter by the ER. BCK estrogen induction is dependent on the DNA-binding domain and transactivation domain TAF2 of the ER. However, direct DNA binding is probably not required. Taken together, these results suggest a novel mechanism for ER-mediated gene activation. This mechanism is consensus ERE independent and cell type specific and requires interactions between the ER and molecules capable of interacting with the BCK promoter TA-rich region.
Mol Cell Biol 1994 Nov
PMID:A novel, cell-type-specific mechanism for estrogen receptor-mediated gene activation in the absence of an estrogen-responsive element. 793 28

The 2-phenylindole system has proved to be a versatile structure for the design of potent antiestrogens, especially when functional groups have been introduced into the alkyl side chain in position 1. In analogy to steroidal structures such as ICI 164,384 a number of 2-phenylindoles with carbamoylalkyl and aminoalkyl side chains were synthesized. They bind to the calf uterine estrogen receptor with relative binding affinities between 2.1 and 21 (estradiol = 100). The antiestrogenic effect of these compounds was demonstrated by the inhibition of transcriptional activity which was measured in a new luciferase assay with the EREwtc luc as reporter plasmid. The derivative with a methyl-n-propyldodecanamide side chain (4h) antagonized the effect of estradiol (10(-9) M) completely at concentrations of 10(-7) M and higher. As a sensitive model for quantification of estrogenic and antiestrogenic effects in vitro we used HeLa-cells cotransfected both with the reporter plasmid and estrogen receptor expression vectors HEG0 and HE0. In cells transfected with these vectors transcriptional activity was strongly dependent on side chain structure. With mutated receptors we were able to show that this activity was mainly due to TAF-1 whereas TAF-2 remained silent. When we studied the effect of some of the new compounds in vivo using the mouse uterine weight assay, we observed a correlation between transcriptional activity in transfected HeLa cells and estrogenic effects in mice. Two of the 1-carbamoylalkyl-2-phenylindoles (4f, 4h) proved to be "pure" antiestrogens both in vitro and in vivo. In estrogen-sensitive MCF-7 breast cancer cells, they strongly inhibit cellular growth. Some of the IC50-values were close to 10(-8) M.
J Steroid Biochem Mol Biol 1994 May
PMID:1-Carbamoylalkyl-2-phenylindoles: relationship between side chain structure and estrogen antagonism. 800 39

Functional expression of opioid receptors was detected in the Xenopus oocyte translation system by a voltage-clamp recording. After injection of poly(A)+ RNA isolated from 3-week-old rat striatum or whole brain, the oocytes often demonstrated intracellular Ca(2+)-mediated oscillatory responsiveness to [D-Ala2, N-methyl-Phe4, Gly5-ol]enkephalin (DAMGO), [D-Pen2, D-Pen5]enkephalin (DPDPE) and U50488H at a concentration of 1 microM. These responses were very transiently expressed after injection of the mRNA, however, water-injected oocytes never responded to any of these opioid agonists. After fractionation by a sucrose-density gradient, an RNA size of about 3-4 kb encoded these opioid receptors. In the oocytes injected with size-selected striatal mRNA, DPDPE evoked the fluctuating current with higher probability and larger amplitude than other agonists, whereas oocytes injected with size-selected whole brain mRNA produced DAMGO and U50488H responses predominantly. The DPDPE response of striatal mRNA-injected oocytes was antagonized by naloxone as well as the delta-specific antagonist ICI 174864. The DAMGO and U50488H responses have not been characterized yet because of a strong desensitizing property making repeated recordings impossible. These observations suggest that putative mu, delta and kappa subtypes of opioid receptors mobilizing intracellular Ca2+ are expressed in Xenopus oocytes by rat brain mRNA.
Brain Res Mol Brain Res 1994 Mar
PMID:Functional expression of Ca(2+)-mobilizing opioid receptors in Xenopus oocytes injected with rat brain mRNA. 801 95

The brain isozyme of creatine kinase (CKB) is a major component of the estrogen-induced proteins in the rat uterus. Hormonal specificity of this response was studied in cotransfection assays using the rat CKB promoter linked to the bacterial chloramphenicol acetyltransferase gene. Response was specific for estrogen as 17 beta-estradiol in the presence of estrogen receptor dramatically stimulated the CKB promoter. This induction was completely blocked by the estrogen antagonist ICI 164,384. Nuclear receptors for progesterone, androgen, glucocorticoid and vitamin D did not significantly activate the CKB promoter in the presence of their respective ligands. Creatine kinase (CK) activity was analyzed in decidualized mouse uterus to assess estrogenic activity in vivo. Upon oil stimulation, uterine horns of day 4 pseudopregnant mice underwent a dramatic outgrowth in response to endogenous progesterone. This response was accompanied by a significant decrease in CK activity from a control value of 1.44 +/- 0.25 to 0.38 +/- 0.08 IU/mg protein (P < 0.001), indicating that the action of estrogen was suppressed. Treatment of females one day prior to oil-stimulation with progesterone receptor antagonists, RU486 (Mifepristone) or ZK299 (Onapristone), or with a monoclonal antibody to progesterone (DB3), abolished decidualization, and also restored the CK activity to the control value. These results suggest that CK can be used as a specific cellular marker to detect unopposed estrogen action in the mouse uterus associated with progesterone withdrawal or receptor blockade.
J Steroid Biochem Mol Biol 1994 Jun
PMID:Creatine kinase activity as an indicator of unopposed estrogen action in the mouse uterus associated with anti-progesterone treatment. 803 8

The interaction between the recombinant human estrogen receptor and a variety of nonsteroidal estrogens was studied using a transient transfection assay in mammalian cells. Eight naturally occurring compounds were confirmed to stimulate the transcriptional activity of the human estrogen receptor and to compete for the binding of radiolabeled 17 beta-estradiol to this protein. In order of biological potency, these were zearalenone, beta-zearalenol, coumestrol, genistein, daidzein, phloretin, formononetin, and biochanin A. As with steroidal estrogens, the hormonal activity of these compounds was specific for the estrogen receptor and sensitive to inhibition by 4-hydroxytamoxifen and ICI-164,384. Evidence is also presented to indicate that the stimulatory activity of genistein is unrelated to the protein tyrosine kinase inhibitory activity of this isoflavone. These results demonstrate that a significant number of structurally diverse plant and fungal secondary metabolites exist in nature that may contribute to the total estrogen exposure of the human population.
J Steroid Biochem Mol Biol 1994 Jun
PMID:Interaction of naturally occurring nonsteroidal estrogens with expressed recombinant human estrogen receptor. 803 11

The effects of androgens, antiandrogens, and other steroid hormones on growth of the human prostate cancer cell line LNCaP were studied. Despite the absence of receptors for progesterone and estradiol, the growth rate of the androgen responsive LNCaP-FGC cells increased when cultured in the presence of either estrogens or progestagens. In addition, most antiandrogens were also growth stimulators. This aberrant response was due to a threonine to alanine substitution at amino acid position 868 in the steroid binding domain of the androgen receptor (AR). Only the antiandrogen ICI 176,334 could block transcription and cell growth by the mutant receptor. By immunoprecipitation of the AR from LNCaP cells with the specific antibody F39.4.1 and Western blotting, three types of heat-shock proteins co-precipitated: hsp90, hsp70 and hsp56. This co-isolation could be prevented by pre-incubating the cells with androgens or with the antiandrogen hydroxyflutamide. Only the antiandrogen ICI 176,334 could block the effect of androgens on complex dissociation and prevent tight nuclear binding of the AR. Hydroxyflutamide could only inhibit tight nuclear binding of the wild-type AR. Therefore, in LNCaP cells the mutation in the steroid binding domain of the AR prevents a blockade of receptor function by most antiandrogens, but not by ICI 176,334, probably because of a different mechanism by which this compound blocks receptor function.
J Steroid Biochem Mol Biol 1994 Jun
PMID:Studies on the human prostatic cancer cell line LNCaP. 804 98


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