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)

Prostaglandins (PGE1, PGE2, PGA1) and histamine have opposing effects on gastric HCl secretion, but we found that both stimulate adenylate cyclase activity in cell-free membrane preparations of guinea pig gastric fundic mucosa. The stimulatory effect of prostaglandins was found in this study to be specific and dose-dependent over a concentration range from 10(-7) to 10(-4) M. In similar preparations from antral regions of guinea pig gastric mucosa, the adenylate cyclase was stimulated only by PGE1, PGE2, and PGA1 and not by histamine. Maximum stimulating doses of PGE1, PGE2, or PGA1, and of histamine had an additive effect on the adenylate cyclase activity from fundic gastric mucosa. Metiamide, a histamine H2-receptor antagonist, inhibited the stimulation of fundic mucosa adenylate cyclase by histamine but did not interfere with the stimulation by prostaglandins. Cyclic AMP phosphodiesterase activity of guinea pig gastric mucosa was unaffected by PGE1 and PGE2 or by histamine, and was slightly depressed by PGA1. These results indicate that histamine and prostaglandins stimulate two different adenylate cyclase systems both present in guinea pig gastric mucosa tissue. Therefore, the known inhibitory effect of prostaglandins on gastric acid secretion is not related to the interference with the stimulation of the histamine H2-receptor-sensitive adenylate cyclase complex by histamine nor do prostaglandins accelerate cyclic AMP breakdown by cyclic AMP phosphodiesterase to reduce cyclic AMP levels.
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PMID:Interaction of prostaglandins and histamine with enzymes of cyclic AMP metabolism from guinea pig gastric mucosa. 18 55

Prostaglandins (PG) of the E series and catecholamines stimulate adenosine 3':5'-monophosphate (cAMP) formation in human astrocytoma cells (1321N1). These two classes of effectors activated adenylate cyclase upon interaction with different receptor systems. No evidence for a mediatory role for PG in the action of catecholamines was found. PG interacted with 1321N1 cells with an order of potency of PGE1 = PGE2 greater than PGA1 greater than PGF2 alpha. The effect of combinations of the various PG indicated that all efficacious PG interacted with a common receptor. 7-Oxa-13-prostynoic acid and indomethacin were shown to be competitive inhibitors of the effect of PGE1 with Ki values of 4 and 150 micron, respectively. These two compounds did not inhibit the effect of isoproterenol. Polyphloretin phosphate caused a complex pattern of inhibition of the effects of PGE1 and at higher concentrations also inhibited the effects of isoproterenol. The mefenamate class of nonsteroidal anti-inflammatory agents was found to inhibit the effects of PGE1 with a potency order of meclofenamic acid greater than flufenamic acid = mefenamic acid. The inhibitory action of meclofenamic acid was complex involving specific, but partial, insurmountable antagonism of PGE1 as well as competitive inhibition of PGE1 effects. At higher concentrations of meclofenamic acid a nonspecific inhibition of the effects of both PGE1 and isoproterenol was observed. These studies suggest that the inhibition by nonsteroidal anti-inflammatory agents of the physiological effects of PGE1 in animals may occur, at least in part, at the level of adenylate cyclase. The possibility that multiple classes of adenylate cyclase-linked PGE receptors might exist in nature is discussed.
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PMID:Stimulation of adenosine 3':5'-monophosphate formation by prostaglandins in human astrocytoma cells. Inhibition by nonsteroidal anti-inflammatory agents. 19 79

Incubation of dog thyroid slices with 1 mU/ml TSH resulted in enhanced intracellular and extracellular cAMP accumulation. In the absence of TSH, the intra- and extracellular cAMP concentrations remained at a constant low level. The release of cAMP from TSH-stimulated slices was inhibited by 10 microM PGA1, 1 mM probenecid or 1 mM IBMX, which are known inhibitors of cAMP escape in several tissues. Negative controls of intracellular cAMP levels are exerted in the dog thyroid by 10 microM carbamylcholine (shown to activate a Ca++- calmodulin dependent phosphodiesterase), 100 microM norepinephrine and 100 microM iodide (both inhibiting adenylate cyclase activity). The purpose of the present study was to demonstrate that these three agents do not enhance cAMP escape. The results presented here show that these agents decrease both intracellular accumulation and escape in parallel. Moreover, the escape constants obtained by numerical simulation were not greater in the presence of inhibiting concentrations of carbamylcholine, norepinephrine or iodide. Thus the inhibition by these agents of cAMP accumulation in TSH-stimulated dog thyroid slices cannot be explained by a stimulation of cAMP escape from these cells.
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PMID:The escape of cyclic AMP from dog thyroid slices exposed to positive and negative regulators. 242 18

1. Membrane currents were recorded from voltage clamped Xenopus laevis oocytes, still surrounded by follicular cells, theca and enveloping inner ovarian epithelia (ovarian follicles). 2. Superfusing follicles with frog Ringer solution containing E-series prostaglandins (PGE1 or PGE2) or oxytocin (0.5-2 microM) generated slow membrane currents arising from an increase in membrane conductance to K+. 3. Follicles taken from different frogs varied greatly in responsiveness to PGE and oxytocin. For example, enclosed oocytes with good sensitivity to prostaglandins responded to 1 nM-PGE, whereas follicles from some frogs failed to respond at 5 microM. 4. Oocytes with good responsiveness to PGE also produced K+ currents to PGA1, PGA2, PGB1, 11-deoxy-PGE1 and 11-beta-PGE2, whereas PGF2 alpha, PGI2, PGD2 and 8-iso-PGE1 generally failed to elicit membrane currents. 5. Responses to PGE and oxytocin were mimicked by the adenylate cyclase activator forskolin or by intraoocyte pressure injection of cyclic nucleotides. Responses were potentiated by the phosphodiesterase inhibitors theophylline and 3-isobutyl-1-methylxanthine (IBMX). In IBMX (0.5 mM), human atrial natriuretic factor (ANF) (10-60 nM) elicited a similar K+ conductance. This all implied that cyclic nucleotides played a role in the receptor-channel coupling mechanism of these responses. 6. Defolliculating oocytes effectively abolished responses to prostaglandins, oxytocin and ANF, suggesting that the currents arise in follicular cells. 7. The responses of PGE, oxytocin and ANF thus resembled currents elicited by catecholamines, adenosine, gonadotrophins and vasoactive intestinal peptide (VIP). However, PGE, oxytocin and ANF responses were not blocked by catecholaminergic or purinergic antagonists. Moreover, when comparing follicles isolated from different frogs, the sensitivity to PGE and oxytocin varied independently of that to gonadotrophin or VIP. These experiments suggest that Xenopus ovarian follicles contain specific and distinct receptors for PGE, oxytocin and ANF. 8. Acetylcholine attenuated the cyclic nucleotide-mediated K+ responses, including currents elicited by PGE, oxytocin and ANF. Attenuation was not dependent on, or mimicked by, activation of the inositol phosphate-diacylglycerol messenger pathways located in the oocyte itself, nor was it appreciably blocked by loading follicle-enclosed oocytes with 0.1-1.5 mM-EGTA.
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PMID:Membrane currents elicited by prostaglandins, atrial natriuretic factor and oxytocin in follicle-enclosed Xenopus oocytes. 248 34

In the present paper we have examined the properties of the prostaglandin E (PGE) receptor in a transplantable rat Leydig cell tumour (H-540). It appears that PGE1 and PGE2 share a common receptor in membrane particles from this Leydig cell tumour. From saturation analysis and modified Hofstee plots, the specific binding sites for PGE1 can be divided into a high (25%) and low affinity state (75%) with apparent equilibrium constants of dissociation (Kd) of 2.4.10(-7) mol/l and 4.4.10(-6) mol/l, respectively. Association rate kinetics at different temperatures employing 5.10(-9) mol/l [3H]PGE1 showed that specific binding was time- and temperature-dependent. At 37 degrees C an apparent steady state was achieved after approximately 4 h incubation. The binding of [3H]PGE1 was very tight and no dissociation was observed at 20 degrees C during the first 20 h. The free PGE1 receptor appears to be very unstable. Binding was reduced rapidly by storage at 0 degrees C, by freezing and thawing of membrane particles, and by incubation of concentrated membrane particles. Specificity curves showed that PGA1 and PGA2 displaced [3H]PGE1 from receptor to a somewhat lesser degree than PGE2 and PGE1, whereas PGs of the B, D, I and F series had little or no effect. The fact that inhibition of [3H]PGE1 binding by cold PGE1 occurred in the same concentration range as PGE1 activation of adenylate cyclase, indicates that the specific binding of PGE observed here represents functional receptors coupled to the adenylate cyclase.
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PMID:A transplantable rat Leydig cell tumour. Properties of the prostaglandin E receptor. 254 91

The effect of several prostaglandins (PGs) on osteoblastic cells was investigated using clone MC3T3-E1 under serum-free conditions. PGA1, A2, B1, and B2 had little effect on intracellular cAMP, alkaline phosphatase (ALP) activity, and DNA synthesis in the cells. At 4-2000 ng/ml, PGE1 among PG analogs tested had a dose-dependent stimulatory effect on ALP activity in the cells, and this effect was amplified by isobutyl methylxanthine. Also, PGE1 strongly augmented the amount of intracellular cAMP over the same concentration range. However, PGE1 had little effect on ornithine decarboxylase activity and DNA synthesis, and at high doses it rather depressed DNA synthesis. Furthermore, PGE1 did not affect the intracellular cGMP level. The effect of PGE1 on the cells closely mimics that of forskolin, suggesting that the PG stimulates the differentiation of the osteoblastic cells predominantly via the stimulation of adenylate cyclase. In contrast with PGE1, PGF2 alpha strongly increased ornithine decarboxylase activity and DNA synthesis in the cells in a dose-related fashion at low concentrations (4-100 ng/ml), at which concentrations it had little effect on the intracellular cAMP or cGMP level and depressed ALP activity. Moreover, PGF2 alpha depressed the stimulatory effect of PGE1 on ALP activity but did not affect the elevation of cAMP level by PGE1. The accumulation of inositol phosphates was greatly increased by PGF2 alpha in the concentration range effective in stimulating DNA synthesis, but was increased little by PGE1, suggesting that PGF2 alpha is a potent stimulator of phosphatidyl inositol turnover in the cells. In addition, A23187, a Ca ionophore, alone did not influence the DNA synthesis, but the effects of tetradecanoyl phorbol acetate, a direct activator of protein kinase C, were very similar to those of PGF2 alpha. Moreover, the stimulation of DNA synthesis or the inhibition of ALP activity by PGF2 alpha was partially counteracted by H-7, a strong inhibitor of protein kinase C. These results suggest that PGF2 alpha stimulates the proliferation of osteoblastic cells predominantly through the phosphatidyl inositol turnover system following in part the activation of protein kinase C. Our data presented here indicate that PGE1 and PGF2 alpha are closely involved in the differentiation and proliferation, respectively, of osteoblasts in vitro and that their action may be mediated by second messengers which differ from each other.
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PMID:Prostaglandin E1 and F2 alpha stimulate differentiation and proliferation, respectively, of clonal osteoblastic MC3T3-E1 cells by different second messengers in vitro. 282 76

The regulation of murine mammary tumor virus (MuMTV) production by mammotropic hormones, hormonomimetic substances, and cyclic nucleotides was investigated. The virus produced in control and treated mammary tumor cell cultures was quantitated by measuring the supernatant reverse transcriptase activity in exogenous reaction using poly(rC).oligo(dG) as template-primer. Two days after exposure, the synthetic glucocorticoid, dexamethasone (DXMT), increased spontaneous MuMTV production at optimal concentration (0.1 mumol) up to ten times. Dibutyryl derivative of cyclic AMP had no effect on spontaneous MuMTV production, whereas the drug potentiated suboptimal concentrations of the glucocorticoid. Natural prostaglandins, potent agonists of adenylate cyclase catalyzing intracellular synthesis of cyclic AMP, enhanced both basal (up to five times) and DXMT-stimulated (up to 1.6 times) MuMTV replication. The MuMTV-stimulating activity of prostaglandins decreased in the order of PGA1 greater than PGE1 greater than PGB1 greater than PGF2 alpha. Prostaglandins can be replaced partially by norepinephrine and isoproterenol by enhancing the DXMT-mediated MuMTV stimulation, whereas these drugs remained without effect on spontaneous MuMTV production. Theophylline, an antagonist of cAMP-phosphodiesterase converting cAMP to AMP, enhanced the virus-stimulating activity of DXMT as well as of prostaglandins. The enhancement of MuMTV production by adenylate cyclase agonists do not correlate absolutely with the estimates of intracellular cAMP levels, since the highest amounts of cAMP has been repeatedly observed in cells treated with PGE1 and norepinephrine. The results indicate that besides hormones, other hormone-like substances and cyclic nucleotides may be involved in the complex mechanism of hormone-regulated MuMTV genome expression.
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PMID:Role of natural prostaglandins in the control of murine mammary tumor virus expression. 628 Dec 84

The properties of basal and prostaglandin (PG)-stimulated adenylate cyclase of membrane preparations of P388D1 cells were investigated. Three partially purified membrane fractions were obtained by sucrose density gradient centrifugation at the final step of purification from crude homogenate. About 96% of the basal and 89% of PGE2-stimulated adenylate cyclase activity in the homogenate were recovered in three membrane fractions. Two lighter membrane fractions (I and II), which were enriched 11-fold and 8.4-fold in adenylate cyclase activity over crude homogenate, were pooled and subjected to various studies. Results suggested that the basal activity of the membrane preparations has, as in many other cell types, a relatively broad pH optimum (pH 7.5 to 8.5), requires Mg2+, which must be present in excess ATP, and is inhibited by Ca2+. Highly reactive sulfhydryl group(s), which may be present in the lipid bilayer, is required for the adenylate cyclase activity. Because both fluoride ions and GTP augment the enzymatic activity, P388D1 cell membrane adenylate cyclase must possess stimulatory guanine nucleotide-binding protein. The membrane preparations respond to exogeneously added PG by 1.5-fold to 3-fold increase in adenosine 3'-5' cyclic monophosphate (cAMP) production. The magnitude of PG-responsiveness was dependent on the types of PG and the order of potency in stimulation was PGE1 greater than PGE2 greater than PGI2. PGA1, B1, B2, F1 alpha, and F2 alpha stimulated adenylate cyclase only at the highest concentration tested.
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PMID:Properties of prostaglandin-sensitive adenylate cyclase system of a murine macrophage-like cell line (P388D1). 648 Nov 67

Both adenylate cyclase and GTPase activities in human mononuclear cell membranes were increased by prostaglandins. Adenylate cyclase activity, however, was enhanced by much lower concentrations of PGE1 (prostaglandin E1) than were required to increase GTPase. PGE2, PGA1, PGB1, and PGF1 alpha also stimulated GTPase activity. These same prostaglandins, with the notable exception of PGF1 alpha, increased adenylate cyclase activity (PGE2 greater than PGA1 greater than or equal to PGB1). Isoproterenol, 100 microM, doubled adenylate cyclase without altering GTPase activity. Choleragen activated adenylate cyclase in mononuclear cell membranes but had no effect on GTPase activity whether or not PGE1 was present. Mononuclear cells were separated into adherent and nonadherent populations by two different methods to examine the possibility that the prostaglandin-stimulated GTPase was confined to a specific type of mononuclear cell. Adenylate cyclase in membranes from both adherent and nonadherent cells was activated by PGE1, but neither PGE1 nor choleragen altered GTPase activity in these preparations. It appears that, although several prostaglandins can increase GTPase activity in mononuclear cell membranes, the increase in GTPase activity is not consistently associated with activation of adenylate cyclase by prostaglandins.
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PMID:Prostaglandins increase GTP hydrolysis by membranes from human mononuclear cells. 735 71

Our previous studies have implied that prostaglandins inhibit cell growth independent of cAMP. Recent reports, however, have suggested that prostaglandin arrest of the cell cycle may be mediated through protein kinase A. In this report, in order to eliminate the role of c-AMP in prostaglandin mediated cell cycle arrest, we use the -49 lymphoma variant (cyc-) cells that lack adenylate cyclase activity. We demonstrate that dimethyl prostaglandin A1 (dmPGA1) inhibits DNA synthesis and cell growth in cyc- cells. DNA synthesis is inhibited 42% by dmPGA1 (50 microM) despite the fact that this cell line lacks cellular components needed for cAMP generation. The ability to decrease DNA synthesis depends upon the specific prostaglandin structure with the most effective form possessing the alpha, beta unsaturated ketone ring. Dimethyl PGA1 is most effective in inhibiting DNA synthesis in cyc- cells, with prostaglandins PGE1 and PGB1 being less potent inhibitors of DNA synthesis. DmPGE2 caused a significant stimulation of DNA synthesis. S-49 cyc- variant cells exposed to (30-50 microns) dmPGA1, arrested in the G1 phase of the cell cycle within 24 h. This growth arrest was reversed when the prostaglandin was removed from the cultured cells; growth resumed within hours showing that this treatment is not toxic. The S-49 cyc- cells were chosen not only for their lack of adenylate cyclase activity, but also because their cell cycle has been extensively studied and time requirements for G1, S, G2, and M phases are known. Within hours after prostaglandin removal the cells resume active DNA synthesis, and cell number doubles within 15 h suggesting rapid entry into S-phase DNA synthesis from the G1 cell cycle block.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cell cycle arrest by prostaglandin A1 at the G1/S phase interface with up-regulation of oncogenes in S-49 cyc- cells. 820 Sep 6


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