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 activation of human platelets by 5-hydroxytryptamine (5-HT) is not accompanied by detectable release of ATP or TXB2. The process is unaffected by cyclooxygenase, thromboxane synthetase or combined cyclooxygenase/lipoxygenase inhibition (suprofen, indomethacin, R 19091, dazoxiben, N.D.G.A, BW755C, esculetin), indicating the absence of involvement of arachidonic acid metabolites. Transmembrane Ca2+-entry blockers (flunarizine, nifedipine, nimodipine) have no effect either, indicating that the activator calcium released by 5-HT comes from intracellular stores. The 5-HT-induced platelet activation is inhibited by stimulators of adenylate cyclase (PGE1, PGE2, isoprenaline, adenosine) and inhibitors of cAMP phosphodiesterase (papaverine, anagrelide, RA233), indicating that also for this type of platelet activation cAMP behaves as a unidirectional, inhibitory regulator.
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PMID:Biochemical mechanisms in 5-hydroxytryptamine-induced human platelet aggregation. 300 59

Evidence exists that a norepinephrine/prostaglandin E2 (PGE2)/cAMP pathway is involved in the regulation of luteinizing hormone-releasing hormone (LHRH) secretion. The aim of the present experiments was to determine if release of LHRH from the immature rat hypothalamus could also be stimulated by activation of protein kinase C. Median eminences from 28-day-old female rats were incubated in vitro with either dioctanoylglycerol (a synthetic diacylglycerol that selectively activates protein kinase C in intact cells) or 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (another protein kinase C activator). Both agents increased LHRH release, the response to dioctanoylglycerol being more pronounced than that to the phorbol ester. This direct activation of protein kinase C was not accompanied by changes in PGE2 formation. Activation of the PGE2/cAMP pathway by either norepinephrine, PGE2, or forskolin (a stimulator of adenylate cyclase) increased LHRH release. Dioctanoylglycerol or phorbol ester in conjunction with either norepinephrine, PGE2 or forskolin resulted in an additive effect on LHRH release suggesting coexistence of both pathways. Phospholipase C, which activates protein kinase C via formation of diacylglycerol, increased the release of both LHRH and PGE2. This suggests that an increase in endogenous phospholipase C activity caused by neurotransmitter inputs may lead to both activation of protein kinase C and PGE2 formation. Blockade of cyclooxygenase activity by indomethacin obliterated phospholipase C-induced PGE2 release. The same treatment reduced the LHRH response by only 50% indicating that protein kinase C activation can cause LHRH release in the absence of PGE2 synthesis. It is suggested that the median eminence of the rat possesses a protein kinase C-dependent pathway that is coupled positively to LHRH release and complements PGE2/cAMP-dependent mechanisms. Norepinephrine, however, does not appear to be the neurotransmitter responsible for activating the protein kinase C pathway. Simultaneous activation of both pathways may provide a mechanism by which a large increase in LHRH secretion occurs, such as in the afternoon of first proestrus.
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PMID:Activation of two different but complementary biochemical pathways stimulates release of hypothalamic luteinizing hormone-releasing hormone. 301 21

Plasma and tissue concentrations of prostanoids PGE2, PGF2 alpha. 6-keto-PGF1 alpha (a stable metabolite of prostacyclin) and TXB2 (a stable metabolite of thromboxane A2) were measured in normal and magnesium-deficient rats. The mean values for prostanoids in plasma were significantly higher in magnesium-deficient rats than in normals (515 +/- 43 vs 296 +/- 31 pg/ml for 6-keto-PGF1 alpha, p less than 0.01, 3700 +/- 322 vs 346 +/- 33 pg/ml for TXB2, p less than 0.001 and 1234 +/- 132 vs 434 +/- 51 pg/ml for PGE2, p less than 0.001). Tissue levels of prostanoids were also significantly higher in magnesium-deficient rats as compared to normals. The increased synthesis of prostanoids is apparently linked to enhanced influx and translocation of Ca++ into the cells. If the adenylate cyclase is inhibited in magnesium deficiency, the lowered c-AMP will permit a high cyclooxygenase activity and a drastic increase in TXB2. It is possible that the changes in prostaglandin synthesis in magnesium deficiency are linked to the development of different diseases.
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PMID:Alteration of prostanoid metabolism in rats with magnesium deficiency. 301 50

The role of prostanoids in the regulation of chick myoblast differentiation has been investigated. At 3 X 10(-6) M, indomethacin and chloroquine specifically inhibit cell fusion. They do not affect cell proliferation, alignment, or the expression of two muscle-specific proteins, namely, the acetylcholine receptor and the muscle-specific form of creatine phosphokinase. The results demonstrate that it is indomethacin's activity as an inhibitor of prostaglandin synthesis at the cyclooxygenase step that causes the block of cell fusion, whereas chloroquine probably acts at the earlier step of phospholipase A. Prostaglandin E1 (PGE1), but not prostaglandin E2 (PGE2), rapidly reverses the inhibition of fusion imposed by indomethacin or chloroquine. The dose response of the myoblasts to PGE1 is a bell-shaped curve with a 100% reversal of fusion at approximately 10(-9) M. Eicosatrienoate and linoleate reverse the inhibition of fusion with similar kinetics, whereas arachidonate is completely ineffective. The ability of PGE1 and eicosatrienoate but not PGE2 and arachidonate to restore fusion to control levels implies that fusion is specifically regulated by a prostanoid of the one series. The reversal of the fusion-block by linoleate further suggests that this fatty acid provides the necessary source of eicosatrienoate in the myoblast plasma membrane. At 10(-8) M and above, PGE1 and PGE2 stimulate adenylate cyclase and depress control fusion as does 10(-5) M isoproterenol. The beta-adrenergic blocker propranolol abolishes both isoproterenol's inhibition of myoblast fusion and its activation of adenylate cyclase. The similar depressions imposed on cell fusion by 10(-8)-10(-6) M prostanoid and 10(-5) M isoproterenol suggest that in both cases the depressive effects are mediated by cyclic AMP. It is concluded that a prostanoid of the one series regulates fusion by a cyclic AMP-independent mechanisms.
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PMID:Myoblast fusion is regulated by a prostanoid of the one series independently of a rise in cyclic AMP. 301 99

Addition of the cyclooxygenase inhibitor indomethacin to human synovial cells in culture, at concentrations which completely block prostaglandin E2 (PGE2) synthesis, reversibly inhibited the interleukin-1 (IL-1) stimulation of cell-associated and extracellular plasminogen activator (PA) production. Results of mixing experiments suggested that the inhibition by indomethacin was not due to stimulation of production and/or activation of a PA inhibitor, but reflected inhibition of PA synthesis. Simultaneous addition of PGE2 or dibutyryl cAMP prevented the inhibition by indomethacin. Addition of the phosphodiesterase inhibitor, theophylline, the adenylate cyclase stimulator, forskolin, or dibutyryl cAMP caused an enhancement of the IL-1 induction of synovial cell PA. These results suggest that the IL-1 induction of synovial cell PA occurs via generation of endogenous PGE2 and cAMP.
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PMID:Evidence that interleukin-1 induction of synovial cell plasminogen activator is mediated via prostaglandin E2 and cAMP. 301 58

Data indicating that the 21-kDa protein (p21) Harvey-ras gene product shares sequence homology with guanine nucleotide-binding proteins (G proteins) has stimulated research on the influence(s) of p21 on G-protein-regulated systems in vertebrate cells. Our previous work demonstrated that NIH-3T3 mouse cells expressing high levels of the cellular ras oncogene isolated from the EJ human bladder carcinoma (EJ-ras) exhibited reduced hormone-stimulated adenylate cyclase activity. We now report that in these cells another enzyme system thought to be regulated by G proteins is inhibited, namely phospholipases A2 and C. NIH-3T3 cells incubated in plasma-derived serum release significant levels of prostaglandin E2 (PGE2) as determined by radioimmunoassay when exposed to platelet-derived growth factor (PDGF) at 2 units/ml; the levels of PGE2 released from EJ-ras-transfected cells are only 3% those of controls despite a similar basal (unstimulated) release from control and EJ-ras-transfected cells. The lack of PDGF-stimulated PGE2 release from EJ-ras-transfected cells is not due to a defect in the prostaglandin cyclooxygenase enzyme, since incubation of control cells and EJ-ras-transfected cells in 0.33, 3.3, or 33 microM arachidonate resulted in identical levels of PGE2 release. The lack of PDGF-stimulated PGE2 release from EJ-ras-transfected cells also does not result from the loss of functional PDGF receptors. EJ-ras-transformed cells bind 70% as much 125I-labeled PDGF as control cells and are stimulated to incorporate [3H]thymidine and to proliferate after exposure to PDGF. Moreover, this inhibition is not likely the result of a secondary cellular effect related to the transformed phenotype, since NIH-3T3 cells transformed by v-src released PGE2 at wild-type levels after exposure to PDGF. Determination of total water-soluble inositolphospholipids and changes in the specific activities of phosphatidylcholine in control and EJ-ras-transfected cells demonstrated that PDGF-stimulated phospholipase C and A2 activities are inhibited in the EJ-ras-transfected cells.
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PMID:Loss of platelet-derived growth factor-stimulated phospholipase activity in NIH-3T3 cells expressing the EJ-ras oncogene. 309 98

Previous studies from our laboratory have shown that in vivo cyclooxygenase blockade in dogs unmasks the antidiuretic agonist activity associated with the vasopressin antagonist, SK&F 101926, and have revealed two new vasopressin analogs, SK&F 104146 and 105494, with greatly reduced antidiuretic agonist activity. The purpose of the present study was to characterize SK&F 104146 and SK&F 105494 for water diuretic activity (aquaretic activity) in hydropenic dogs and for antagonism of vasopressin-stimulated antidiuresis in hydrated dogs. The vasopressin receptor affinity and inhibition of vasopressin-stimulated adenylate cyclase activity in renal membranes were also studied. When administered to hydropenic dogs, SK&F 101926 (3 or 30 micrograms/kg) did not cause a water diuresis. Substitution of the dipeptide tail of SK&F 101926 with Arg7D-Arg8NH2 (SK&F 104146; 30 micrograms/kg) was associated with a reduction of urine osmolality from 1876 +/- 182 to 349 +/- 94 mOsm/kg of H2O, and an increase in free water clearance (from -0.32 +/- 0.09 to 0.06 +/- 0.09 ml/min). Replacement of the 1 to 6 disulfide bridge of SK&F 104146 with a 1 to 6 dicarba bridge (SK&F 105494; 3 micrograms/kg) was associated with a further reduction of urine osmolality (1709 +/- 281 to 210 +/- 79 mOsm/kg of H2O) and a net positive free water clearance (from -0.56 +/- 0.02 to 0.6 +/- 0.35 ml/min). In water diuretic dogs, SK&F 104146 and 105494 shifted the vasopressin dose-response for antidiuresis to the right. SK&F 105494 appeared to be 3 times more potent than SK&F 104146.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:SK&F 105494: a potent antidiuretic hormone antagonist devoid of partial agonist activity in dogs. 320 22

E-series prostaglandins have previously been demonstrated to inhibit hormone-stimulated glycogenolysis when added to isolated hepatocytes of the rat. In the present study, the effect of nonsteroidal anti-inflammatory drugs, which inhibit cyclo-oxygenase activity, on glycogenolysis was examined in the hepatocyte model. Ibuprofen (80 microM), indomethacin (50 microM) and meclofenamate (60 microM) all increased rates of glycogenolysis when added under basal conditions. In contrast, piroxicam (50 microM) had no effect on glycogenolysis in the hepatocyte system. Concentrations of ibuprofen below 80 microM did not significantly increase rates of glycogenolysis. Ibuprofen (80 microM) had no effect on glycogenolysis in the presence of 10(-5)M adrenaline or 5 X 10(-7)M glucagon, but did increase glycogenolytic rates in the presence of 5 X 10(-8)M glucagon. Ibuprofen-stimulated glycogenolysis was inhibited by addition of prostaglandin E2 (PGE2). Under conditions where glucagon-stimulated glycogenolysis was inhibited by exogenous PGE2, addition of ibuprofen (80 microM) increased the rate of glycogenolysis. Ibuprofen had no effect on basal or glucagon-stimulated hepatocyte adenylate cyclase activity. In conclusion, these results demonstrate that nonsteroidal anti-inflammatory drugs which are carboxylic acids can increase the rate of glycogenolysis in isolated hepatocytes. The high concentrations of drug required to stimulate glycogenolysis, the lack of effect of piroxicam, and the demonstration of stimulation by ibuprofen in the presence of exogenous PGE2 all suggest that the stimulation of glycogenolysis by ibuprofen, indomethacin and meclofenamate is independent of cyclooxygenase inhibition. These observations are consistent with reports that carboxylic acid nonsteroidal anti-inflammatory drugs can interfere with hepatic intracellular calcium handling.
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PMID:Effect of nonsteroidal anti-inflammatory drugs on glycogenolysis in isolated hepatocytes. 386 82

The action of pharmacologic agents on chymase-induced exocytosis of beta-hexosaminidase and arachidonic acid (AA) metabolism by rat serosal mast cells (RSMC) was determined and compared with their effects on anti-IgE induced activation. Indomethacin (INDO) (less than or equal to 10 microM), a cyclooxygenase inhibitor, did not affect chymase- or anti-IgE-mediated exocytosis, while completely inhibiting prostaglandin D2 (PGD2) release at 1.25 microM. Theophylline (THEO), mepacrine, 3-amino-1-[m-(trifluoromethyl)-phenyl]-2-pyrazoline (BW755C), and diethylcarbamazine (DEC), inhibitors of adenosine binding and phosphodiesterases, phospholipases, AA metabolism, and vesicular transport as well as leukotriene A4 formation, respectively, inhibited exocytosis with ID50 values of 3.4, 0.22, 3.4 and 1.9 mM for chymase and 2.4, 0.17, 2.8 and 5.2 mM for anti-IgE. These agents inhibited net PGD2 release with ID50 values of 2.1, 0.04, less than 0.05, and 1.5 mM for chymase and of 0.5, 0.1, less than 0.05, and 4 mM for anti-IgE. 5,6-Dehydroarachidonic acid (DHA) and arachidonyl hydroxylamine (AH), 5-lipoxygenase inhibitors, did not affect chymase-mediated exocytosis; anti-IgE-mediated exocytosis was not altered by AH but was suppressed by DHA (ID50 = 20 microM). Nordihydroguaiaretic acid (NDGA), an antioxidant, inhibited chymase-mediated exocytosis dose-dependently (ID50 less than or equal to 13.3 microM) while decreasing anti-IgE-mediated exocytosis by only 30% at 2.5-20 microM; net PGD2 release induced by both stimuli was inhibited dose-dependently. 2',5'-Dideoxyadenosine (DDA) and 1,6-di(0-(carbamoyl)cyclohexanone oxime)hexane (RHC 80267) and inhibitors of adenylate cyclase and of di-triglyceride lipases, respectively, had little effect on exocytosis induced by chymase but inhibited that induced by anti-IgE with ID50 values of 0.4 mM and 37 microM, respectively. With DDA the inhibition of net PGD2 release occurred with anti-IgE but not chymase, whereas RHC 80267 inhibited both chymase and anti-IgE-mediated PGD2 release. Differential inhibition of activation-secretion suggests either that chymase provides a step inhibited in IgE-mediated exocytosis by DDA, RHC 80267 and DHA, or that the activating pathway initiated by chymase is distinct.
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PMID:Pharmacological modulation of activation-secretion of rat serosal mast cells by chymase, an endogenous secretory granule protease. 393 69

Resident rat peritoneal macrophages (M0) were more active in metabolising exogenous arachidonic acid (AA) to prostaglandin E2 (PGE2) than starch elicited cells. Basal levels of cAMP were lower in elicited macrophages than in resident cells but the adenyl cyclase of elicited macrophages was much more readily stimulated by cyclooxygenase products formed from exogenous AA than resident cells. AA injected into carrageenin sponge granulomas reduced the severity of the inflammation in a dose related manner.
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PMID:Antiinflammatory aspects of exogenous arachidonic acid. 608 27


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