Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pharmacological study of the blood-brain barrier has often been hampered by the unavailability of a large number of pure and fully differentiated brain capillary endothelial cells. Here we describe a homogeneous culture of brain capillary endothelial cells isolated from bovine brain (BBECs), which retain at least some phenotypic characteristics of the functional blood-brain barrier: intracellular tight junctions and monoamine oxidase activity. These cells were subcultured in vitro, in the absence of any neuronal or glial influences, for greater than 100 doublings without any sign of senescence. The present study is focused on the expression of beta-adrenergic receptors on BBECs. By Northern blot hybridization, subtype-specific ligand binding, and cyclic AMP accumulation experiments, we demonstrate that beta 1- and beta 2-adrenergic receptors are coexpressed (in the respective proportions of 42 and 58%) on BBEC membranes and are functionally coupled to adenylate cyclase. This is the first report documenting a significant number of beta 1-adrenergic receptors on brain capillary endothelial cells. The results are discussed in light of the known noradrenergic innervation of brain capillaries.
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PMID:Coexpression of beta 1- and beta 2-adrenergic receptors on bovine brain capillary endothelial cells in culture. 184 83

The genes coding for three pharmacologically distinct subtypes of human beta-adrenergic receptors (beta 1 AR, beta 2 AR and beta 3 AR) were transfected for expression in Chinese hamster ovary (CHO) cells. Stable cell lines expressing each receptor were analyzed by ligand binding, adenylate cyclase activation and photoaffinity labeling, and compared to beta AR subtypes observed in previously described tissues, primary cultures and transfected cell lines. Each of the three receptor subtypes displayed saturable [125I]iodocyanopindolol-binding activity. They showed the characteristic rank order of potencies for five agonists, determined by measuring the accumulation of intracellular cAMP. These recombinant cell lines express a homogeneous population of receptors and display the known pharmacological properties of beta 1 AR and beta 2 AR, in human tissues. It is therefore likely that the pattern of ligand binding and adenylate cyclase activation, mediated by the new beta 3 AR in CHO cells, also reflects the yet-undetermined pharmacological profile in humans.
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PMID:Expression of three human beta-adrenergic-receptor subtypes in transfected Chinese hamster ovary cells. 184 18

Pretreatment of intact striatal neurons from the mouse embryo in primary culture with 17 beta-oestradiol (10(-9) M), 24 hours) enhanced the stimulation of adenylate cyclase activity induced by either dopamine (D1 receptors), isoproterenol, serotonin or 2-chloroadenosine (maximal effective concentrations) but suppressed inhibitory responses evoked by agonists of D2-dopaminergic or enkephalin (mu and delta) receptors. Binding studies indicated that some of these effects are (beta 1) or are not (D1 and D2) associated with changes in the number of receptors. Similar effects were partially seen with testosterone but not with 17 alpha-oestradiol, progesterone or dexamethasone and those induced by 17 beta-oestradiol were abolished when cells were exposed to inhibitors of mRNA transcription (alpha-amanitin) or protein synthesis (cycloheximide). Modifications in the properties of Gs or Go,i proteins were postulated because the number of adenylate cyclase catalytic subunits was not affected by 17 beta-oestradiol pretreatment. Results of ADP-ribosylation experiments with cholera toxin or pertussis toxin and of immunoblot experiments with anti-G alpha o and anti-G beta sera led us to suggest that 17 beta-oestradiol induces qualitative modifications in Go,i proteins leading to a stabilization of the associated form of the heterotrimer G alpha o,i beta gamma. In fact, pretreatment with pertussis toxin (which impairs G alpha o,i beta gamma dissociation) mimics the effects of 17 beta-oestradiol on responses of adenylate cyclase to stimulatory and inhibitory agonists.
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PMID:In vitro effects of 17 beta-oestradiol on the sensitivity of receptors coupled to adenylate cyclase on striatal neurons in primary culture. 196 97

Reports in the literature have suggested that a complex alteration in beta-receptor pathway takes place in failing human myocardium. The purpose of our study was to evaluate the beta-adrenergic receptor system in an experimental model of heart failure induced by monocrotaline in rats. Monocrotaline, administered with a single intraperitoneal injection (50 mg/Kg), causes pulmonary hypertension and right ventricular hypertrophy, associated with congestive heart failure. beta 1 and beta 2-receptors were characterized in the right ventricle by direct radioligand binding utilizing [125I] Iodocyanopindolol and selective beta 1-(CGP 20712A) and beta 2-(ICI 118551) antagonists. Adenylate cyclase was measured in basal condition and in the presence of different stimulators as isoproterenol with ICI 118551 (beta 1-receptor-stimulated activity), isoproterenol with CGP 20712A (beta 2-receptor-stimulated activity), Gpp(NH)p, NaF and forskolin. In the right ventricle of the failing hearts the beta 1-receptor density decreased selectively (-55.8%) while the beta 2-receptor density was unchanged. Modifications in the adenylate cyclase system were demonstrated: a reduction in the basal and beta 1- and beta 2-stimulated adenylate cyclase activity; a decrease in adenylate cyclase activation elicited by Gpp(NH)p, but not by forskolin and NaF. In conclusion, these data suggest that in monocrotaline-induced heart failure in the rat there is a selective beta 1-receptor down-regulation and an impaired coupling efficiency of G proteins. These results are in line with biochemical changes found in patients with heart failure.
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PMID:[The adrenergic beta system in an experimental model of heart failure]. 196 56

The purpose of this study was to explore alterations in the life cycle of adrenergic receptors and the Gs protein in the heart of ischemic animals. In initial experiments left anterior descending coronary artery occlusion was performed in guinea pigs. Sarcolemmal (SL) and light vesicle (LV) (presumably intracellular) fractions were prepared. Both fractions contained a substantial number of beta-adrenergic receptors and alpha 1-adrenergic receptors: the relative proportion of beta-adrenergic receptors in LV/SL was greater than for alpha 1-adrenergic receptors. Myocardial ischemia produced a rapid externalization of beta-adrenergic receptors from LV to SL. alpha 1-adrenergic receptors also increased in SL but without an apparent externalization from LV. Pretreatment of animals with either the non-selective beta-antagonist propranolol or the beta 1-selective antagonist atenolol increased the number of SL beta-receptors and blunted the ischemia-induced increase in SL beta-adrenergic receptors. Treatment with the partial agonist pindolol did not cause up-regulation of beta-receptors, and did not block ischemia-induced externalization. In the second part of this study, we have begun to examine post-receptor events in a rat model of myocardial ischemia. Ligation of the distal left main coronary artery in the rat led to an increase in SL beta-receptors. As G proteins play a pivotal role in transducing receptor occupancy to activation of effector molecules, we measured levels of Gs which stimulates adenylate cyclase activity, using an ELISA technique. In rat SL the amount of alpha s markedly decreased within 15 min of coronary occlusion. There was no transfer of Gs activity to the light vesicle fraction. These studies indicate the dynamic nature of adrenergic receptors and the alpha s protein in the sarcolemma in myocardial ischemia. Changes in adrenergic receptor number and in G protein expression may contribute to the altered pathophysiology of the ischemic heart.
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PMID:Beta-adrenergic receptors and the Gs protein in myocardial ischemia and injury. 196 4

In the normal heart the ratio of beta 1/beta 2-receptors in both atria and ventricles is about 75:25; in the failing heart the ratio is about 60:40. Stimulation of either beta 1- or beta 2-receptors results in a positive chronotropic and inotropic response. In the periphery, with the exception of lipolysis, renin release, control of intraocular pressure and intestinal relaxation, beta 2-related activity predominates. The nature of the beta 2-receptor is being unravelled and it has now been cloned. The beta-receptor antagonist is 'anchored' via disulfide bonding. Subsequent events involve the regulatory protein guanine nucleotide which couples the receptor to adenylate cyclase. beta-receptor density may by up- or down-regulated. beta-stimulation down-regulates (uncouples and internalizes or sequestrates) and beta-antagonism up-regulates beta-receptor numbers, but the functional implications of such changes are not always clear. A partial agonist occupies a receptor site and competitively inhibits the full agonist (e.g. noradrenaline). A partial agonist differs from a full agonist in that maximal response of a tissue is less. When background sympathetic activity is absent or very low a partial agonist will act as an agonist, e.g. increase heart rate, but when background tone is high the partial agonist will behave functionally as an antagonist, e.g. decrease heart rate. In animals partial agonist activity (PAA) can be assessed in many ways. In the catecholamine-depleted (reserpine or syrosingopine), vagotomized or pithed, intact animal beta-activity can be assessed via changes in heart rate, cardiac contractility and atrioventricular conduction. Isolated organs can also be used such as atria, papillary muscle, tracheal, mesenteric artery and uterine preparations. The choice of animal is important as marked species differences in response can occur. In man assessing PAA is difficult due to the presence of an intact sympathetic system: the problem can be overcome by autonomic blockade of constrictor and vagal reflexes with prazosin, clonidine and atropine but leaving the beta-receptor mediated responses unimpaired. beta 1- and beta 2-selective PAA can also be gauged via an increased sleeping heart rate (basal sympathetic tone) in the presence and absence of a beta 1- and beta 2-selective antagonist. beta 1-selective PAA can also cause an increase in resting systolic blood pressure, beta 2-selective PAA may be further assessed by a fall in DBP, increased blood flow, fall in peripheral resistance or increased finger tremor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Measurement and cardiovascular relevance of partial agonist activity (PAA) involving beta 1- and beta 2-adrenoceptors. 196 43

The aim of the study was to analyse the beta 2-adrenoceptor selectivity earlier found in two series of catecholamines and one series of resorcinolamines (Johansson et al. 1986). The affinity of the compounds was assessed in binding studies in preparations from the guinea-pig left heart ventricle (beta 1-adrenoceptors) and the soleus muscle (beta 2-adrenoceptors) using 3H-CGP-12177 as radioligand. Further, the activation of the adenylate cyclase by the compounds was studied in the same preparations. Selectivity quotients were obtained from both functional effects and from affinity and adenylate cyclase activating studies. There was a good correlation between the selectivity quotients obtained in these two ways. Tertiary butyl substitution on the amino nitrogen gave the highest beta 2-adrenoceptor selectivity in both the catechol and resorcinol series. In comparison with their isopropyl substituted analogues the beta 2-adrenoceptor selectivity of these compounds (KWD 2026 and terbutaline) was mainly due to a change in affinity for the beta 1- and beta 2-adrenoceptors and, to a lesser degree, a change in intrinsic efficacy.
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PMID:An analysis of the beta 2-adrenoceptor selectivity in three series of beta-adrenoceptor agonists. 197 Jun 32

We determined the relative contribution of beta 1- and beta 2-adrenoceptor stimulation to the positive inotropic responses of human atrial myocardium to catecholamines. (-)Norepinephrine produced stimulation predominantly through beta 1-receptors and (-)epinephrine through both beta 1- and beta 2-receptors. However, there were marked differences in the responses of tissues from patients treated with the beta 1-selective antagonist atenolol compared with non-beta-blocker-treated patients; surprisingly, beta 2-mediated responses were enhanced, and beta 1-mediated responses were unaltered. There was an enhanced responsiveness to (-)epinephrine (atenolol treated: -log M EC50, 7.57 +/- 0.07; non-beta-blocker treated: -log M EC50, 6.77 +/- 0.17; p less than 0.001), and the relative importance of beta 2-adrenoceptor stimulation was increased for both (-)norepinephrine and (-)epinephrine. In tissues from atenolol-treated patients, salbutamol, a beta 2-selective partial agonist, had an enhanced potency and a greater intrinsic activity (atenolol treated: -log M EC50, 7.13 +/- 0.09; intrinsic activity, 0.86 +/- 0.04; non-beta-blocker treated: -log M EC50, 5.76 +/- 0.44; intrinsic activity, 0.39 +/- 0.13). We investigated possible mechanisms underlying the enhanced responsiveness to beta 2 stimulation. Determination of beta 2-adrenoceptor affinity for salbutamol showed no change of affinity in atenolol-treated patients. Responses of the tissues to the cyclic AMP analogue dibutyryl cyclic AMP were not different between atenolol-treated and non-beta-blocker-treated patients. The results suggest that chronic blockade of beta 1-adrenoceptors causes enhanced coupling of beta 2-adrenoceptors to adenylate cyclase or to other mechanisms leading to increased contractile force.
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PMID:Selective beta 1-adrenoceptor blockade enhances positive inotropic responses to endogenous catecholamines mediated through beta 2-adrenoceptors in human atrial myocardium. 197 35

The beta adrenergic activation of adenylate cyclase was examined in membrane homogenates of rat interscapular brown adipose tissue (IBAT). In control membranes, isoproterenol and norepinephrine (NE) stimulated adenylate cyclase with activation constants of about 20 and 300 nM, respectively. Exposure of rats to 4 degrees C for 3 days increased the maximal stimulation of adenylate cyclase to these agonists but did not alter the respective activation constants. The beta 1-selective antagonist 1-(2-cyanophenoxy)-3-beta-(3-phenylureido)ethylamino-2-pr opa nol blocked isoproterenol stimulation of adenylate cyclase in control and cold-exposed membranes at a concentration 100 times lower than did the beta 2-selective antagonist erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobuta n-2-ol. These data indicate that typical adrenergic agonists stimulate IBAT adenylate cyclase via beta 1 receptors. (R*,R*)-4-[2-[2 [9 3-chlorophenyl)-2-hydroxyethyl]amino)propyl) phenyl]phenoxyacetic acid (BRL 37344), an atypical agonist with activity at the beta 3 receptor, stimulated adenylate cyclase in control membranes with an activation constant of approximately 700 nM. Membranes of cold-exposed rats exhibited a high affinity response to BRL 37344 similar to that seen in control membranes and, in addition, a low affinity response. BRL 37344 stimulation of adenylate cyclase was unaffected by 1-(2-cyanophenoxy)-3-beta-(3-phenylureido)ethyl-amino-2-prop anol, whereas stimulation by NE or epinephrine was potently blocked.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Norepinephrine and BRL 37344 stimulate adenylate cyclase by different receptors in rat brown adipose tissue. 197 40

Pretreatment of guinea pigs with adrenaline, isoprenaline or terbutaline for 7 days significantly reduced the Bmax for the radioligand [125I]cyanopindolol (ICYP) in the gastrocnemius muscle (beta 2-adrenoceptors). Pretreatment of guinea pigs with terbutaline reduced the responsiveness of gastrocnemius muscle slices adenylate cyclase to isoprenaline (10(-4) M). In the left ventricle (predominantly beta 1-adrenoceptors) pretreatment of guinea pigs with isoprenaline or adrenaline for 7 days did not alter the Bmax for ICYP. The responsiveness of adenylate cyclase to isoprenaline (10(-4) M) in left ventricle slices was significantly reduced following isoprenaline pretreatment of the guinea pigs. Thus desensitisation of beta-adrenoceptors in left ventricle and skeletal muscle developed following chronic agonist pretreatment. Reduction of beta 2-adrenoceptors in the skeletal muscle could be responsible for the desensitisation of adenylate cyclase. In the left ventricle the receptors were resistant to agonist induced down-regulation. It is proposed that other mechanisms which are tissue- and species-specific independent of the receptor subtype can be responsible for agonist-induced desensitisation in the left ventricle of the guinea pig in vivo.
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PMID:Regulation of beta-adrenoceptors in the guinea pig left ventricle and skeletal muscle following chronic agonist treatment. 197 85


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