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 presence of a beta-3 adrenoceptor (in addition to the classical beta-1 and beta-2 adrenoceptors) and its involvement in the control of heart rate was investigated in the dog. Experiments were carried out in conscious normal and sinoaortic denervated dogs (i.e. animals deprived of baroreceptor pathways). In normal dogs, infusion of isoproterenol, BRL 37344 (4-[-[(2-hydroxy-(3-chlorophenyl) ethyl)-amino]propyl]phenoxyacetate) (a beta-3 adrenergic agonist) or CGP 12177 (4-[3-t-butylamino-2-hydroxypropoxy]benzimidazol-2- one) (a beta-1 beta-2 adrenergic antagonist reported to act as an agonist for the beta-3 adrenergic receptor) increased heart rate with an order of potency: BRL 37344 > isoproterenol >> CGP 12177. [125I]Cyanopindolol binding (2-2000 pM) was saturable and Scatchard analysis indicated the presence of an homogenous population of binding sites. KD was 12.8 +/- 18.5 pM and maximum binding was 94.2 +/- 12.5 fmol/mg of protein. Competition binding studies on dog heart membranes using 150 pM [125I] cyanopindolol indicated an order of potency (CGP 12177 > isoproterenol > BRL 37344) different from that observed in cardiovascular studies. Isoproterenol stimulated adenylate cyclase activity in heart membranes from normal dogs, whereas CGP 12177 and BRL 37344 were without any stimulating action. The positive chronotropic effects of isoproterenol, BRL 37344 and CGP 12177 were accompanied with a reduction in arterial blood pressure. In sinoaortic denervated animals, isoproterenol infusion provoked tachycardia and hypotension. BRL 37344 and CGP 12177 were without any significant effect on heart rate but induced a rapid and dramatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The positive chronotropic effect induced by BRL 37344 and CGP 12177, two beta-3 adrenergic agonists, does not involve cardiac beta adrenoceptors but baroreflex mechanisms. 136 69

The pharmacological properties of BRL 37,344 (sodium-4-(2'-[2-hydroxy-2- (3-chloro-phenyl)ethylamino]-propyl)phenoxyacetatesesquihydrate), a beta 3-selective agonist, and CGP 12,177A) (-)-4-(3-t-butyl amino-2-hydroxypropoxy) benzimidazole-2-one], a non-selective beta-antagonist, recently characterized as a partial beta 3-agonist in rat adipose tissue, were studied in comparison with isoproterenol, a non-selective beta-agonist, in plasma membranes prepared from the livers of newborn rats. Competition binding curves obtained with [125I]iodocyanopindolol ([125I]CYP) as ligand and isoproterenol or BRL 37,344 as competitor were characterized by the presence of a high and a low affinity binding site; the high affinity binding site was no longer detectable when guanidylimidobisphosphate (GppNHp) was present in the incubation mixture. Competition curves with CGP 12,177A were monophasic and independent of GppNHp. In the presence of 10(-7) M of the beta 2-selective antagonist ICI 118,551 [erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylamino butan-2-ol], a concentration which blocks most of the beta 2-receptors, ligand binding was reduced to 32% of its maximum. Under these conditions, isoproterenol further displaced the ligand, and competition curves still displayed the high and the low affinity binding sites; BRL 37,344, however, caused no further displacement of ligand, except at the highest concentrations. This suggests that BRL 37,344 occupies only the ICI 118,551-sensitive binding sites, i.e. beta 2-receptors. Isoproterenol and BRL 37,344 both stimulated adenylate cyclase (EC 4.6.1.1) activity concentration dependently, although the stimulating effect of BRL 37,344 was about half of what was found for isoproterenol. Furthermore, BRL 37,344 inhibited concentration dependently the isoproterenol-induced stimulation of adenylate cyclase, and the inhibition was dependent on the concentration of isoproterenol. The stimulating effect of isoproterenol and BRL 37,344 on adenylate cyclase was blocked by ICI 118,551, whereas the beta 1-selective antagonist CGP 20,712A ((+/-)-(2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino)-3-[4-(1-methy l-4- trifluoromethyl-2-imidazolyl)-phenoxy]-2-propanolmethane sulphonate) was ineffective. CGP 12,177A failed to stimulate adenylate cyclase activity. From these results we suggest that BRL 37,344 acts as a beta 2-partial agonist in rat liver. The results obtained with CGP 12,177A are typical for a non-selective beta-antagonist. We therefore conclude that there is no pharmacological evidence for the presence of beta 3-receptors in livers from newborn rats.
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PMID:Pharmacological characterization of a beta 3-receptor agonist (BRL 37,344) and a partial agonist (CGP 12,177A) in neonatal rat liver plasma membranes. 136 33

Exposure of C62B rat glioma cells to fresh medium containing fetal bovine serum induced a sensitization of the subsequent ability of isoproterenol and forskolin to stimulate cyclic AMP accumulation, compared to cells exposed to fresh medium without serum. Isoproterenol stimulation was typically increased by 2- to 4-fold and forskolin stimulation by 3- to 5-fold. Sensitization occurred rapidly, was rapidly reversible and appeared to result from an increase in maximal stimulation. A commercial preparation of albumin, purified chromatographically so as to retain bound lipids and other factors, was able to mimic the effect of serum. In contrast to the effects of serum, exposure of cells to phorbol 12-myristate, 13-acetate induced little or no change in forskolin stimulation but a marked desensitization of isoproterenol stimulation that was due primarily to a decrease in potency. Neither the protein kinase C inhibitor staurosporine or overnight exposure to phorbol 12-myristate, 13-acetate to down-regulate protein kinase C prevented serum-induced sensitization. Pertussis toxin almost completely blocked serum-induced sensitization, suggesting involvement of a pertussis toxin-sensitive guanine nucleotide-binding protein in mediating the effects of serum. Sensitization was poorly retained in membrane adenylate cyclase assays. Studies with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, direct assays of cyclic AMP degradation by intact cells and assays of phosphodiesterase activity in cell lysates all indicated that degradation of cyclic AMP was decreased in serum-pretreated cells. Thus, both increased cyclic AMP synthesis and decreased cyclic AMP degradation may contribute to sensitization in these cells.
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PMID:Serum-induced sensitization of cyclic AMP accumulation in C62B rat glioma cells. 138 77

We recently reported that cultured gland serous cells release chondroitin sulfate proteoglycans (CSPGs) in response to beta-adrenergic agonists. In this study, we analyzed this regulatory pathway and other cellular mechanisms responsible for CSPG secretion. We show the following. 1) Isoproterenol increased CSPG secretion in a concentration-dependent manner, with maximal stimulation (50%) obtained at 10(-5) M; at this concentration, the beta-agonist also stimulated protein kinase A (PKA) by 50%, whereas it increased cellular adenosine 3',5'-cyclic monophosphate (cAMP) content by 300%. 2) Phenylephrine (10(-5) M), 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (1.6 x 10(-7) M), and A23187 (10(-6) M) also stimulated CSPG secretion; this stimulation was concomitant with protein kinase C (PKC) translocation from cytosol to membrane, was blocked by sphingosine (2 x 10(-5) M), and was additive with that elicited by isoproterenol. 3) All PKC activators potentiated the isoproterenol-induced increased in cAMP accumulation without modifying the activation of PKA elicited by the beta-agonist. Our results indicate that although the signaling pathways triggered by alpha- and beta-adrenergic agonists converge at the level of adenylate cyclase in tracheal serous cells, PKA and PKC independently regulate CSPG secretion.
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PMID:Regulation of secretion in cultured tracheal serous cells by protein kinases A and C. 165 65

The beta-adrenoceptor-sensitive adenylate cyclase in primary cultures of rat striatal neurons was inhibited by opioids, unlike that in rat striatal slices. Isoprenaline (1 microM)-stimulated cyclic AMP production was dose dependently inhibited by the mu-opioid receptor agonist. [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO, EC50 = 0.02 microM, 36% inhibition), and only slightly reduced by relatively high concentrations of the delta-opioid receptor agonist, [D-penicillamine2, D-penicillamine5]enkephalin (DPDPE, 1 microM). The highly selective and potent delta-opioid receptor agonist. [D-Ser2(O-tert-butyl),Leu5]enkephalyl-Thr6 (DSTBULET), and the kappa-opioid receptor agonist, U50-488, were ineffective in concentrations up to 3 microM. Naloxone reversed equally well the inhibitory effects of DPDPE and of DAGO, indicating the involvement of functional mu-opioid receptors. The isoprenaline (1 microM)-stimulated adenylate cyclase activity in cultured glial cells, which exceeded that in neurons about 10-fold, was not affected by opioids. Therefore, opioids were ineffective in rat brain slices probably due to the fact that cyclic AMP production induced by beta-adrenoceptor activation occurs primarily in the glial cells, where it is not subject to inhibition by opioids. These data indicate for the first time the existence of an interaction between functional mu-opioid receptors and beta-adrenoceptors on striatal neurons of the rat.
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PMID:Beta-adrenoceptor-sensitive adenylate cyclase is inhibited by activation of mu-opioid receptors in rat striatal neurons. 165 67

Individuals with mitral valve prolapse (MVP) frequently show symptoms of a hyperadrenergic state. beta adrenergic receptor characteristics were compared in the lymphocytes of subjects with symptomatic MVP and control subjects during rest and exercise. At rest, the proportion of receptors binding agonist with high affinity, as determined from isoproterenol competition for (-)[125I]-iodopindolol binding sites, was greater in MVP subjects than in controls. With exercise, the proportion of high-affinity receptors in MVP subjects decreased to control levels. Isoproterenol stimulation of lymphocyte 3',5'-cyclic adenosine monophosphate (cyclic AMP) also was greater in MVP subjects than in controls at rest, but not during exercise. Plasma catecholamine concentrations in MVP subjects were normal during both rest and exercise. Unlike exercise, isoproterenol infusion elicited clinical manifestations of increased adrenergic responsiveness in MVP subjects. The beta receptor in exercised MVP subjects exhibited unusually high affinity agonist binding (i.e. a lower dissociation constant KH than in either the same subjects at rest or exercised controls) and also abnormal coupling to the stimulatory guanine nucleotide-binding regulatory protein (GS) of adenylate cyclase, as reflected by the inability of guanine nucleotide to convert the receptor to a low-affinity state. These findings suggest that functional alteration of the beta adrenergic receptor, in the absence of abnormal plasma catecholamine levels, might contribute to the hyperadrenergic state of MVP subjects at rest. However, desensitization of high affinity beta receptors or altered receptor-GS coupling might preserve normal adrenergic responsiveness during exercise.
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PMID:Altered beta adrenergic receptor function in subjects with symptomatic mitral valve prolapse. 165 43

Fat-cells were isolated from patients of body-mass indices (BMIs) ranging from 17.9 to 83.9 kg/m2. Isoprenaline-stimulated cyclic AMP accumulation in cells prepared from obese subjects as compared with normal-weight subjects, was less sensitive to inhibition by the adenosine agonist N6-(phenylisopropyl)adenosine (PIA) (P = 0.047). The inhibition of 7 beta-desacetyl-7 beta-[gamma-(N-methylpiperazino) butyryl]-forskolin-stimulated adenylate cyclase by PIA in the presence of adenosine deaminase was also much attenuated in crude plasma membranes of adipocytes prepared from massively obese patients as compared with lean controls (P = 0.0143). This difference was probably not due to different cell size, because adenylate cyclase of crude plasma membranes of large adipocytes was actually more sensitive to PIA than was adenylate cyclase of membranes of smaller fat-cells co-isolated from the same individual. The stimulatory effect of PIA on glucose uptake in the presence of adenosine deaminase was depressed in adipocytes prepared from obese subjects and correlated with BMI at r = -0.626 (P = 0.007) at 100 nM-PIA. The adenosine receptors were studied by using the adenosine antagonist 1,3-[3H]dipropyl-8-cyclopentylxanthine. The binding was rapid and proportional to protein concentration. There was no difference in the affinities of receptors in membranes of obese and normal-weight subjects; Kd values of all patients averaged 3.3 nM. Bmax values were 54 and 130 fmol/mg of protein in membranes prepared from seven obese and five control patients respectively. The Bmax values calculated per mg of protein correlated with BMI at r = -0.539 (P = 0.047). The adenosine content of adipose tissue was higher in obese than in control subjects. These results demonstrate an attenuated response of cyclic AMP accumulation, adenylate cyclase and glucose uptake to adenosine in fat-cells prepared from obese subjects, and suggest that this change is at least partly due to changes in the amount of adenosine receptors, but not their affinity. The decreased receptor number could be due to higher adenosine content. A higher adenosine concentration in adipose tissue could explain why lipolysis is inhibited in situ in obesity, and the desensitization could explain the diminished response to adenosine analogues in isolated fat-cells.
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PMID:Attenuated adenosine-sensitivity and decreased adenosine-receptor number in adipocyte plasma membranes in human obesity. 165 38

This study assessed agonist- and post-receptor-stimulated adenylate cyclase (AC) activity in parotid and submandibular salivary glands from female F-344 rats of 3, 12, and 24 months of age. Isoproterenol-stimulated dose-response activation of adenylate cyclase was unchanged between 3 and 12 months but decreased at 24 months (p less than .05). Forskolin-stimulated AC activity, representing catalytic unit activity, was decreased at 24 months in the parotid (p less than .05) and at 12 months (p less than .05) and 24 months (p less than .01) in the submandibular gland. Beta-adrenergic signal transduction in salivary glands stimulates the secretion of salivary proteins that have important functions in the maintenance of oral health.
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PMID:Beta-adrenergic signal transduction in aging parotid and submandibular salivary glands. 165 13

An endothelium-derived 21-residue peptide, endothelin, has been shown to be a constrictor of arteriolar smooth muscle. This study investigated the effect of endothelin on isolated pulmonary veins and arteries using tissue bath techniques. Endothelin elicited concentration-dependent contractions and maximal responses were equal in magnitude to those of phenylephrine (PE) or norepinephrine (NE). Responses to endothelin were long lasting and persisted despite repeated washing. The following agents had no significant effect on endothelin-induced contractions: FPL 55712 (1 microM), indomethacin (10 microM), methysergide (3 microM), phentolamine (3 microM), pyrilamine (3 microM) and the putative thromboxane A2 receptor antagonist SQ 29,548 (3 microM). Moreover, removal of the endothelium did not alter responses to endothelin. Isoproterenol, forskolin, and 8-bromo-cAMP had a differential inhibitory effect on matched contractions induced by endothelin and the putative thromboxane A2 receptor agonist U-46619. Isoproterenol (0.1 microM) relaxed endothelin and U-46619 contractions by 2 +/- 1% and 74 +/- 5%, respectively; forskolin (3 microM) by 12 +/- 3% and 84 +/- 9%, respectively and 8-bromo-cAMP (10 mM) by 23 +/- 8% and 82 +/- 9%, respectively. Likewise, 10 microM sodium nitroprusside relaxed endothelin contractions by 32 +/- 4% and PE contractions by 80 +/- 9%. Endothelin is a very potent pulmonary vasoconstrictor that appears to have a direct effect on vascular smooth muscle. Compared to U-46619 or PE, endothelin-induced contractions are highly resistant to relaxing agents that increase either cAMP or cGMP. Moreover, resistance to cAMP does not appear to involve inhibition of adenylate cyclase.
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PMID:Functional antagonism in rabbit pulmonary veins contracted by endothelin. 166 30

A given overall level of beta-adrenergic receptor occupancy by agonist can involve either high or low turnover of occupancy with respect to individual receptors, depending on the binding properties of the particular agonist. It was recently demonstrated that, for epinephrine-stimulated adenylate cyclase activation in the S49 cell, a portion of the separation between the beta-adrenergic receptor binding curve and the cyclase response curves is dependent on high occupancy turnover (high binding frequency). By involving a larger number of receptors within a short period of time than are bound at any one instant, the effect of high binding frequency is to increase the rate of GTP-binding protein/adenylate cyclase activation over the rate that is observed when the mobility of the number of receptors occupied at any given instant is the rate-limiting factor. This phenomenon contributes to the normal dose-response curve for epinephrine, according to our analysis, but only in combination with the apparent high efficiency of the receptor in the epinephrine-bound state at cyclase activation. Here we examined the potential combination of the contributions of agonist binding frequency and intrinsic efficiency to the adenylate cyclase activation rate for four other beta-adrenergic agonists (isoproterenol, zinterol, metaproterenol, and dobutamine). This was done by a comparison of the response (1-min cAMP accumulation) between a point on the normal dose versus response curve (control) with the response under conditions in which the concentration of agonist-bound receptors was identical to control but the absolute number of receptors involved in maintaining that concentration was significantly reduced. In the experiments, the majority of the receptors were blocked by the beta-adrenergic antagonist propranolol, which has a relatively long occupancy half-life. The remaining receptors were occupied by agonist such that the concentration of bound receptors was identical to the control condition of low occupancy of the full complement of receptors in the absence of antagonist. Compared with control, the experimental condition was one in which agonist occupancy turnover was inhibited and the potential contribution of agonist binding frequency as a factor contributing to the cyclase activation rate was greatly reduced (producing a point on the receptor mobility-limited dose versus response curve). Isoproterenol and metaproterenol show evidence that their binding frequencies and the efficiency of the receptor when bound to them are of such a combination that the normal dose-response curves for these agonists contain a component that is dependent on the binding frequency.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Comparisons of the combined contributions of agonist binding frequency and intrinsic efficiency to receptor-mediated activation of adenylate cyclase. 167 53


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