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)

Two prostaglandins, prostaglandin E1 (PGE1) and prostaglandin B1 (PGB1), block S-phase DNA synthesis in synchronous cultured baby hamster kidney (BHK) cells. The prostaglandin inhibition of DNA synthesis does not appear to require elevated levels of cAMP. In BHK-21 cells that have been "desensitized" to prostaglandin stimulation of adenylate cyclase and, therefore, have control levels of cAMP, PGE1 retains its inhibitory effect on the incorporation of tritiated thymidine into DNA. When BHK cells are exposed to PGB1 (a prostaglandin that does not elicit a cAMP response), DNA synthesis is also blocked. In nonsynchronous cells exposed for 1 h to PGE and then incubated for 1 h with PGE removed, a rebound of DNA synthesis occurs, therefore providing evidence that a transient rise of cAMP in itself is not capable of causing a cascade of reactions that block the synthesis of DNA. In addition, the concentration of PGE required for inhibition of DNA synthesis is significantly less than that required for cAMP generation. Addition of 1 x 10(-8) M PGE to BHK cells can be shown to significantly inhibit DNA synthesis within 30 min, with half-maximal inhibition seen at 3 x 10(-7) M PGE. Cyclic AMP levels for controls were 4.9 +/- 0.2 and 4.6 +/- 0.1 for 1 x 10(-6) M PGE1. These findings suggest that the prostaglandins can act independently of cAMP at physiological concentrations; and, therefore, it is possible that prostaglandins have a physiological role in the control of cell growth during S-phase.
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PMID:Evidence for cAMP-independent inhibition of S-phase DNA synthesis by prostaglandins. 629 10

Deficient activity of the guanine nucleotide regulatory protein (G unit), an integral component of the membrane-bound adenylate cyclase complex, has been implicated as the biochemical lesion in many patients with pseudohypoparathyroidism (PHP) type I. In addition to renal resistance to parathyroid hormone in this disorder, there is decreased responsiveness of diverse tissues to hormones that act via 3',5'-cyclic AMP (cAMP). To assess whether a deficiency of G units could account for impaired adenylate cyclase activity, we studied cAMP production in intact cultured fibroblasts and fibroblast plasma membranes from five patients with PHP in response to several activators of adenylate cyclase. The number of G units in PHP fibroblast membranes, measured by cholera toxin-dependent [(32)P]ADP ribosylation of G-unit peptides, as well as the G-unit activity, determined by the ability of detergent extracts to reconstitute adenylate cyclase activity in G-unit-deficient S49 CYC(-) membranes, were found to be markedly reduced compared with control membranes (43 and 40%, respectively), The activation of fibroblast membrane adenylate cyclase by effectors that act directly through the G unit (guanosine triphosphate, guanosine 5'-0-[3-thiotriphosphate] [GTP-gamma-S], NaF) was significantly greater in control membranes than in membranes from patients with PHP. Moreover, we found that hormone (prostaglandin E(1)) stimulated adenylate cyclase activity was also greater in control membranes than in PHP membranes. Neither the apparent affinity of membrane adenylate cyclase for GTP-gamma-S (apparent K(m) =5 X 10(-8) M) nor the rate of enzyme activation by GTP-gamma-S was significantly different in fibroblast membranes from control subjects and patients with PHP. In contrast to the notable differences in hormone and G-unit-activated adenylate cyclase shown in fibroblast membranes from PHP patients and control subjects, the intrinsic catalytic activity of membranes, as determined by forskolin-stimulated adenylate cyclase, was not significantly different in the two groups. Intact fibroblasts derived from patients with PHP accumulated significantly (P 0.001) less cAMP (46+/-21 pmol cAMP/mcg DNA, n = 5) than cells from normal individuals (170+/-51 pmol cAMP/mcg DNA, n = 11) when stimulated with PGE(1). PGE(1)-stimulated accumulation of cAMP by intact fibroblast monolayers correlated closely with PGE(1) plus GTP-activated membrane adenylate cyclase activity in both patients and controls (r = 0.97, P < 0.001). Our data show that, in patients with PHP, (a) fibroblast membranes show a decreased complement of G units, (b) membrane catalytic activity is normal, but adenylate cyclase activity is reduced when stimulated by hormone or by effectors which activate the G unit, (c) the ability of cells to accumulate cAMP in response to hormone stimulation is reduced, and (d) reduced membrane adenylate cyclase activity correlates well with impaired cellular cAMP synthesis. These results, taken together, indicate that a deficiency of G-unit activity can impair synthesis of cAMP by both intact and broken cells, and may explain the resistance of multiple tissues to hormones that act via cAMP observed in PHP.
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PMID:Deficient guanine nucleotide regulatory unit activity in cultured fibroblast membranes from patients with pseudohypoparathyroidism type I. a cause of impaired synthesis of 3',5'-cyclic AMP by intact and broken cells. 630 48

Topical application of prostaglandin E1 or E2 onto the mouse skin results in a 2- to 3-fold increase of the cyclic AMP level in epidermis within 5 min. (15S)-15-methyl-PGE1 is more active in this respect, whereas PGD2 and PGF2 alpha are ineffective. The level of cyclic GMP is not altered by E- or F-prostaglandins. A single PGE2 application desensitizes the cyclic AMP response of mouse epidermis to further treatments in a dose dependent and agonist-specific manner. Delayed and longlasting refractoriness of PGE2-induced cyclic AMP accumulation is also caused by hyperplasiogenic skin irritants such as the phorbol ester tumor promoter TPA or the nonpromoting agents RPA and A23187. The non-irritant skin mitogen 4-O-methyl-TPA does not evoke desensitization. TPA-induced PGE2 refractoriness cannot be prevented by inhibitors of protein synthesis, anti-inflammatory steroids, indomethacin or phentolamine. The development of tachyphylaxis does not seem to be related to endogenous formation of PGE or cyclic AMP. A 2-fold increase of epidermal cyclic AMP observed within 1-2 h of TPA application can be inhibited by indomethacin treatment and correlates with delayed accumulation of PGE2 in TPA-treated epidermis, whilst immediate PGE accumulation (5-10 min after TPA application) which has been shown to be critical for development of TPA-induced epidermal hyperplasia is not accompanied by any change of the intraepidermal cyclic AMP level. It is concluded that mouse epidermis contains two types of PGE-regulated effector systems, one of which is coupled to adenylate cyclase, one of which is not. Only the latter system is involved in the induction of hyperplasia. At least as far as the mitogenic effect is concerned, cyclic AMP does not seem to be involved in TPA action.
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PMID:Prostaglandins, cyclic nucleotides and the effect of phorbol ester tumor promoters on mouse skin in vivo. 631 56

Some metabolic effects of prostaglandins have been related to their alteration of adenosine-3',5'-monophosphate (cyclic AMP) metabolism in different tissues. Prostaglandins E1 and E2 stimulate liver adenylate cyclase in vitro, but conflicting reports have been made about metabolic changes caused by E prostaglandins in hepatic tissue. We have attempted to resolve these issues by comparing the effects of PGE1 with those of glucagon using broken-cell homogenates, intact hepatocytes, liver slices and perfused liver. Prostaglandin E1 (PGE1) increased cyclic AMP in liver slices and in perfused liver without increasing glycogenolysis, but PGE1 had no discernible effect on carbohydrate or cyclic AMP metabolism in isolated hepatocytes. Glucagon caused predictable increases in cyclic AMP and glycogenolysis using hepatocytes, liver slices or perfused liver. These data can be explained by the absence of PGE effects on cyclic AMP metabolism in hepatocytes. The concentration of E prostaglandins (PGEs) increased 1.75-fold during incubations (37 degrees C) of hepatocyte suspensions, but cyclic AMP remained constant. Addition of exogenous arachidonate and indomethacin to cell suspensions increased and decreased PGEs, respectively, but cyclic AMP and glycogen metabolism were unchanged. Arachidonate and indomethacin likewise did not alter glucagon-stimulated glycogenolysis or cyclic AMP biosynthesis. The production of E prostaglandins and cyclic AMP appears to be unrelated in hepatocytes.
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PMID:Dissociation of E prostaglandin effects on liver glycogenolysis and cyclic AMP levels. 631 5

The possibility that prostaglandin E2 (PGE2) increases endometrial vascular permeability and initiates decidualization in sensitized rat uteri by stimulation of adenosine 3':5'-cyclic monophosphate (cAMP) synthesis was investigated. Immature rats, pretreated so that they were sensitized for the decidual cell reaction, were used. Following the unilateral intrauterine injection of 50 microliters phosphate-buffered saline containing gelatin (PBS-G), a deciduogenic stimulus, uterine concentrations of both PGE and cAMP were elevated as early as 1 min after the intrauterine treatment. To determine if uterine stimuli which increase endometrial vascular permeability also increase uterine cAMP concentrations, rats, treated with or without indomethacin, an inhibitor of PG synthesis, received unilateral intrauterine injections of 50 microliters PBS-G with and without 10 micrograms PGE2 and were killed 15 min later. Uterine cAMP concentrations were elevated in all injected horns except in those of indomethacin-treated rats receiving PBS-G intraluminally, thus paralleling the expected changes in endometrial vascular permeability. As indicated by radioactivity levels in the stimulated horn 15 min after the i.v. injection of 125I-labeled bovine serum albumin, the intrauterine injection of dibutyryl cAMP, with or without theophylline, did not increase endometrial vascular permeability in indomethacin-treated animals. In contrast, cholera toxin, an activator of adenylate cyclase activity, markedly elevated permeability and induced decidualization. Except for the lack of a permeability response to the cAMP analogue, these data are consistent with the hypothesis that the effect of PGE2 on endometrial vascular permeability is mediated by cAMP.
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PMID:Prostaglandin E2, adenosine 3':5'-cyclic monophosphate and changes in endometrial vascular permeability in rat uteri sensitized for the decidual cell reaction. 631 67

Ritodrine hydrochloride is a beta-mimetic amine which is used to inhibit premature labor. While the mechanism of action of beta-mimetic drugs is believed to be a function of its action on the adenylate cyclase system, the drug may also act via other mechanisms. We examined the effect of this drug on both contractile activity and prostanoid production using an in vitro preparation of a uterus from a 21-day pregnant rat. Two uterine segments were simultaneously studied in separate incubation chambers. Ritodrine (2.0 mg/ml) was added to one tissue chamber while the other tissue served as a control. Frequency and contractile force were monitored polygraphically for 45 min. Incubation medium was then removed for analysis of prostaglandin E2 (PGE2), PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane B2 (TXB2) by radioimmunoassay. Ritodrine-treated uteri demonstrated a contractile force which was 16.8% of that of the control, a significant decrease. Ritodrine-treated uteri also produced less prostanoids. The greatest effect was on PGE production (27.3% of the control, p less than 0.001). The effect of ritodrine on the other prostanoids was less pronounced (PGF2 alpha, 71%; 6-keto-PGF1 alpha, 84%; TXB2, 67% of the control). The presence of 0.2 mM dibutyryl cAMP in the incubation media also suppressed contractile force; however, prostanoids were not reduced and in some cases were elevated. It is concluded that one effect of ritodrine is a reduction in prostanoid production, predominantly PGE2 and this in part may play a role in the drug's efficacy. The reduction does not appear to be mediated through the adenylate cyclase system.
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PMID:Effect of ritodrine hydrochloride and dibutyryl cyclic AMP on contractile activity and prostanoid production of uteri from pregnant rats in vitro. 632 62

To define sites of prostaglandin action of renal tubules, the distribution of adenylate cyclase sensitive to prostaglandin E2 (PGE2) was examined in single nephron segments dissected from rat kidney. Further, the interaction between PGE2 and vasopressin on adenylate cyclase activity in nephron sensitive to vasopressin was evaluated. Procedures involved in isolating nephron segments were without effects on adenylate cyclase stimulation by PGE2. PGE2 stimulated adenylate cyclase activity of the thin descending limb of Henle (tDL), cortical collecting tubules (CCT), and medullary collecting tubules (MCT) at concentrations of 1.4 x 10(-5) to 2.8 x 10(-5) M. PGE2 was without effects in other nephron segments tested including proximal convoluted tubules, proximal pars recta, the thin and thick ascending limb of Henle's loop, and distal and connecting tubules. PGE2, at both high (2.8 x 10(-5) M) and low (2.8 x 10(-8) M) concentrations, did not inhibit adenylate cyclase activity stimulated by submaximal doses of vasopressin in medullary thick ascending limb of Henle (MTAL), CCT, and MCT. These data define the distribution of PGE-sensitive adenylate cyclase in the rat nephron, i.e., tDL, CCT, and MCT, and show the lack of direct inhibitory actions of PGE2 on vasopressin sensitive adenylate cyclase in MTAL, CCT, and MCT.
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PMID:Distribution of prostaglandin E2-sensitive adenylate cyclase along the rat nephron. 723 66

1 Heparin can produce platelet aggregation in vitro and in vivo; it has been proposed that this may be due to the reported inhibition of the prostaglandin E(1) (PGE(1))-stimulated adenylate cyclase of the platelet by heparin.2 The effect of heparin on the cyclic adenosine 3',5'-monophosphate (cyclic AMP) response to PGE(1) was measured in intact and broken platelets both in vitro and in platelets obtained from normal subjects during intravenous infusion with herapin.3 In platelet lysates, heparin produced a dose-related inhibition of PGE(1)-stimulated adenylate cyclase. The maximum response to PGE(1) was reduced, with half-maximal inhibition occurring at 3 mug/ml heparin. This inhibition could be prevented by protamine sulphate.4 Heparin did not affect PGE(1)-stimulated cyclic AMP production in intact platelets either in vitro or in platelets taken during the infusion of 5,000iu heparin over 2h to 2 normal volunteers. Similarly, preincubation of platelets with heparin for up to 3h at 37 degrees C did not affect platelet adenylate cyclase.5 The effects of heparin were very similar to those of fluoride on the platelet adenylate cyclase: heparin and fluoride increased basal enzyme activity slightly (3-4 fold) but their effects were not additive; both inhibited the response to PGE(1) by approximately 50% when added directly to the assay and the inhibitory effects of the two were not additive; preincubation of membranes with either heparin or fluoride produced an irreversible state of inhibition.6 As heparin inhibits PGE(1)-stimulated adenylate cyclase activity only in broken platelets, we suggest that the aggregatory effects of heparin are probably independent of any action on cyclic AMP production.
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PMID:Inhibition of prostaglandin E1-responsive platelet adenylate cyclase by heparin: a study of the mechanism of inhibition and its relevance to platelet aggregation. 724 63

A fourth PGE receptor subtype, the EP4 receptor, has recently been described in the pig saphenous vein (PSV). Similar to the EP2 receptor, it mediates relaxation and is linked to stimulation of adenylate cyclase. The aim of this study was to determine whether or not the EP receptor present in the rabbit jugular vein (RJV), currently classified as an atypical EP2 receptor, is of the EP4 subtype. The relaxant activities of four EP2 agonists, 11-deoxy PGE1, 16,16-dimethyl PGE2, butaprost, and AH 13205, on the RJV and PSV have been examined, and the effect of the EP4 receptor antagonist AH 23,848B studied. The EP2 agonists showed a similar order of potency on the two preparations. 11-Deoxy PGE1 and 16,16-dimethyl PGE2 were potent agonists on the EP4 receptors of the PSV and on the RJV giving approximately equi-effective concentration ratios (EECs) of 2.0-6.6 and 2.8-9.9, respectively, compared to PGE2 (EEC = 1), and so do not discriminate between EP2 and EP4 receptors. Butaprost was less active on these preparations (EEC 42-43) than on classical EP2 receptors, and AH 13205 was much less active (EEC 3100-2780). While these results suggest that the EP receptors on the RJV are of the EP4 subtype, this was not confirmed using the EP4 receptors antagonist AH 23,848B.
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PMID:Comparison of the EP receptor subtypes mediating relaxation of the rabbit jugular and pig saphenous veins. 766 4

Interleukin 3-dependent BNu-2cl3 mast cells, mucosal type-like mast cells, exhibited a specific high-affinity binding site for [3H]prostaglandin (PG) E2. The binding was completely displaced by M&B 28767, an EP3-selective agonist, but not by EP1- or EP2-selective ligands, indicating that the PGE2 binding site is of the EP3 subtype PGE receptor. Whereas the EP3 subtype is presumed to be coupled to inhibition of adenylate cyclase in various tissues and cells, in BNu-2cl3 cells PGE2 had no ability to inhibit adenylate cyclase activity, while it induced concentration-dependent stimulation of phosphoinositide metabolism and caused an increase in the intracellular free Ca2+ concentration in a pertussis toxin-sensitive manner. PGE2 by itself did not evoke histamine release from the cells, but it markedly stimulated histamine release in concert with ionomycin, a Ca2+ ionophore. The PGE2-stimulated release was also completely blocked by pertussis toxin. Thus, the PGE receptor expressed on BNu-2cl3 mast cells is of the EP3 subtype and is linked to phosphoinositide metabolism via a pertussis toxin-sensitive G protein, and this activation leads to histamine release.
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PMID:Characterization of the prostaglandin E receptor expressed on a cultured mast cell line, BNu-2cl3. 769 May 67


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