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, especially PGE2 and PGI2, appear to participate in the development of inflammatory reactions. While these PGs may act to promote inflammation, they may also inhibit immune reactions; this effect is largely related to stimulation of adenylate cyclase. Human rheumatoid synovial tissue explants and derived adherent synovial cells (ASC) in vitro produce large amounts of PG, primarily PGE2, which may participate in the pathogenesis of rheumatoid inflammation and promote the osteoclastic resorption of juxtaarticular bone. Rheumatoid synovial organ cultures are unusual in that they derive a significant proportion of archidonic acid substrate for the PGE2 synthesis from triglycerides, while ASC utilize primarily phospholipids. Aspirin-like, nonsteroidal anti-inflammatory drugs inhibit PGE2 synthesis by rheumatoid synovial organ cultures at concentrations similar to those achieved in plasma during therapy. Glucocorticoids are also potent inhibitors of PGE2 synthesis, and evidence from experiments with tissue labeled with 1-[14C]arachidonic acid indicates that glucocorticoids do not act to inhibit arachidonic acid release, as has been postulated for other tissues. Human peripheral blood mononuclear cells produce a factor (MCF) that regularly stimulates the production of PGE2 and collagenase from resting ASC often by over 100-fold. The MCF appears to be produced by monocytes, and its production by monocytes is enhanced by lectin-stimulated T-cells. The ability of ASC to respond to exogenous PGE2 stimulation of cAMP synthesis is inhibited or stimulated by factors that increase or decrease PGE2 levels, respectively, in the cultures. The MCF augments the responsiveness of cAMP response to PGE2 in indomethacin-treated cultures. These in vitro experiments suggest that the pathogenesis of rheumatoid inflammation involves interactions between monocyte-macrophages, lymphocytes, and synovial cells regulating the production of PGE2, cAMP, and other factors.
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PMID:Prostaglandins and their regulation in rheumatoid inflammation. 23 4

The effects of aspirin on gastric acid secretion were studied in isolated rabbit parietal cells (PC). Aspirin (10(-5) M) potentiated histamine-, dibutyryl cyclic AMP (dbcAMP)-, forskolin- and 3-isobutyl-1-methylxanthine-stimulated acid secretion without affecting basal acid secretion. Augmentation of secretagogue-stimulated acid secretion by aspirin was dependent on calcium (Ca2+) since potentiation was blocked by removal of extracellular Ca2+ ([Ca2+]o) or addition of the calcium antagonist lanthanum chloride. Using the Ca2+ probe fura-2, aspirin (10(-6) - 2 X 10(-5) M) rapidly increased intracellular free Ca2+ concentration ([Ca2+]i) in a dose-dependent manner. The source of released Ca2+ was intracellular as demonstrated by depletion of intracellular Ca2+ and [Ca2+]o with EGTA washing. Aspirin did not affect several other signal transduction sites involved in stimulus-secretion coupling, including the H2 receptor, intracellular cyclic AMP (cAMP), inositol 1,4,5, triphosphate (IP3) and H+,K(+)-ATPase. Aspirin decreased PC prostaglandin E2 (PGE2) content by 98%. Exogenous dimethyl PGE2 (dmPGE2) inhibited both histamine-stimulated acid secretion and its enhancement by aspirin. In contrast, dmPGE2 abolished aspirin-induced potentiation of dbcAMP-stimulated acid secretion by augmenting the dbcAMP-stimulated response. These results indicate that aspirin acts at a site beyond the adenylate cyclase/cAMP system and before the proton pump, presumably by releasing Ca2+ from an IP3-independent intracellular storage pool and by inhibiting PGE2 generation.
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PMID:Aspirin potentiates prestimulated acid secretion and mobilizes intracellular calcium in rabbit parietal cells. 216 52

1. Exposure of platelets to exogenous arachidonic acid results in aggregation and secretion, which are inhibited at high arachidonate concentrations. The mechanisms for this have not been elucidated fully. In our studies in platelet suspensions, peak aggregation and secretion occurred at 2-5 microM-sodium arachidonate, with complete inhibition around 25 microM. 2. In platelets loaded with quin2 or fura-2, the cytoplasmic Ca2+ concentration, [Ca2+]i, rose in the presence of 1 mM-CaCl2 from 60-80 nM to 300-500 nM at 2-5 microM-arachidonate, followed by inhibition to basal values at 25-50 microM. Thromboxane production was not inhibited at 25 microM-arachidonate. Cyclic AMP increased in the presence of theophylline, from 3.5 pmol/10(8) platelets in unexposed platelets to 8 pmol/10(8) platelets at 50 microM-arachidonate; all platelet responses were inhibited with doubling of cyclic AMP contents. 3. The adenylate cyclase inhibitor 2',5'-dideoxyadenosine attenuated the inhibitory effect of arachidonate, suggesting that it is mediated by increased platelet cyclic AMP and that it is unlikely to be due to irreversible damage to platelets. 4. Aspirin or the combined lipoxygenase/cyclo-oxygenase inhibitor BW 755C did not prevent the inhibition by arachidonate of either [Ca2+]i signals or aggregation induced by U46619. 5. Thus high arachidonate concentrations inhibit Ca2+ mobilization in platelets, and this is mediated by stimulation of adenylate cyclase. High arachidonate concentrations influence platelet responses by modulating intracellular concentrations of two key messenger molecules, cyclic AMP and Ca2+.
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PMID:High concentrations of exogenous arachidonate inhibit calcium mobilization in platelets by stimulation of adenylate cyclase. 245 17

We have shown earlier that abnormal platelet aggregation in spontaneously hypertensive rats (SHR) is not caused by prostaglandins. In this study platelets from SHR and normotensive (Wistar Kyoto, WKY) rats were used to examine the role of phosphoinositides and phosphorylation of 47,000 and 20,000 Dalton proteins in abnormal platelet activation in hypertension. Thrombin (0.05 U/ml) induced a rapid decrease in (32P)-P04 labelled phosphatidylinositol-4, 5-bisphosphate (PIP2), phosphatidylinositol-4-phosphate (PIP) and phosphatidylinositol (PI) in washed rat platelets. However, significantly greater loss of PIP2 and PI was seen in SHR platelets than in WKY platelets. For example the level of PIP2 declined by 32% in SHR platelets and only by 13% in WKY platelets at five seconds of incubation with thrombin. The loss of PI was similar in SHR and WKY platelets for the first five seconds of incubation with thrombin. However, by 15 seconds SHR platelets showed a significantly greater loss (24%) in PI than in WKY platelets (8%). Thrombin induced a 14% and 18% decrease in PIP at three seconds in WKY and SHR platelets respectively. In SHR platelets PIP level returned to the baseline in five seconds and then rose to 20% above the baseline by 30 seconds. In contrast PIP level in WKY platelets slowly reached the basal value by 30 seconds. Thrombin also produced a two- to three-fold greater accumulation of (32P)-phosphatidic acid (PA) in SHR platelets than in WKY platelets. Thrombin (0.05 U/ml) induced rapid phosphorylation of 47,000 Dalton (P47) and 20,000 Dalton (P20) proteins in both WKY and SHR platelets. Thrombin induced a four-fold greater increase in phosphorylation of P47 in SHR platelets than in WKY platelets in the first five seconds. Thrombin produced significantly greater increase in phosphorylation of P20 in SHR platelets (34% and 41%) than in WKY platelets (18% and 28%) at 5 and 15 seconds. Phosphorylation of P20 was followed by dephosphorylation in both WKY and SHR platelets. Aspirin (500 microM) did not affect phosphorylation of either P47 or P20 in SHR or WKY platelets. In other experiments prostaglandin E1 (0.5 microM), which stimulates adenylate cyclase via a guanine nucleotide regulatory protein termed Gs, caused an eighteen-fold increase in cyclic AMP level in SHR platelets as compared to a six-fold increase in WKY platelets. These data lead us to suggest that increased turnover of phosphoinositides and increased phosphorylation of P47 and P20 are involved in abnormal platelet activation in SHR platelets.
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PMID:Thrombin-induced abnormal platelet activation in spontaneously hypertensive rats is linked with phosphoinositides turnover and phosphorylation of 47,000 and 20,000 dalton proteins. 283 38

Bradykinin-stimulated increases in renal prostaglandin (PG) synthesis are thought to result in subsequent increases in cAMP content. This study assesses the relationship between bradykinin-stimulated increases in PGE2 and cAMP syntheses in renal inner medullary slices. Bradykinin-mediated increases in cAMP (2 min) preceded those in PGE2 (5 min) synthesis. Forskolin, an activator of adenylate cyclase, increased cAMP, while 2',5'-dideoxyadenosine, an adenylate cyclase inhibitor, reduced cAMP. However, neither agent altered bradykinin-stimulated PGE2 synthesis. Aspirin decreased basal and abolished bradykinin-stimulated PGE2 production, but did not alter bradykinin-induced increases in cAMP content. Maximal stimulatory concentrations of 1-methyl-3-isobutylxanthine, a cyclic nucleotide phosphodiesterase inhibitor, and bradykinin were additive in their capacity to increase inner medullary cAMP content. These results suggest that 1-methyl-3-isobutylxanthine and bradykinin increase cAMP by separate mechanisms and that bradykinin increases inner medullary cAMP by a direct effect on the production of that cyclic nucleotide. Bradykinin-mediated increases in cAMP and PGE2 syntheses by renal medullary slices are independent effects of this renally acting hormone.
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PMID:Independent effects of bradykinin on adenosine 3',5'-monophosphate and prostaglandin E2 metabolism by rabbit renal medulla. 619 96

Convulxin (Cx), a component of the venom of the snake Crotalus durissus cascavella, induced the concentration-dependent aggregation of guinea-pig platelets when used at and above 50 +/- 5 ng/ml, accompanied by the release of ATP and by the formation of thromboxanes (Tx). Platelet activation by Cx was not due to potential contaminants found in the crude snake venom, such as phospholipase A2 and clotting enzymes. Aspirin (50-100 microM) failed to interfere with the platelet effects of Cx, demonstrating independence from cyclo-oxygenase. In contrast, indomethacin (50 microM) displayed a distinct inhibitory activity on the effects of Cx, as compared to aspirin, and thus exerts cyclo-oxygenase-independent effects on platelet activation. The ADP scavenger creatine phosphate/creatine phosphokinase (CP/CPK) inhibited aggregation by Cx used at concentrations below 6-8 times the threshold, but failed to interfere with higher amounts. Platelet aggregation by Cx was inhibited and reversed once established by EDTA (5mM) and by prostacyclin (0.1-1 microM). Cx-induced activation of platelets is thus Ca2+-dependent and liable to control by the adenylate cyclase-cyclic AMP system. Convulxin induced hypotension, bronchoconstriction and thrombocytopenia when injected i.v. to the anesthetised guinea pig at 0.3-3 microgram/kg. Aspirin and indomethacin (20 and 5 mg/kg respectively) mepyramine and methysergide (02. mg/kg) failed to interfere with these effects, but the combination of either aspirin or indomethacin with methysergide and mepyramine, suppressed the bronchial effects of Cx, leaving the hypotensive and thrombopenic effects unchanged. This synergism remains unexplained. Bronchoconstriction was platelet-dependent, being suppressed by platelet depletion with antiplatelet serum or by i.v. prostacyclin (1-10 microgram/kg).
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PMID:Activation of guinea-pig platelets induced by convulxin, a substance extracted from the venom of Crotalus durissus cascavella. 700 69

In aggregometry studies employing platelet-rich plasma, monoclonal antibody 6D1 (6D1) binds to platelet membrane glycoprotein 1b (GP1b) and has been shown to abolish agglutination with ristocetin (1.5 mg/ml), with little effect on first-phase and slight diminution of second-phase aggregation with adenosine diphosphate (20 mumol/L). In perfusion studies with polyethylene microconduits (PE-100; interior diameter, 0.86 mm; length, 5 cm), platelet deposition (platelets/cm2) is restricted to a patchy monolayer when platelets are treated with 6D1 (10 micrograms/ml), providing a new model to study surface platelet adhesion isolated from platelet aggregation. The power of low-molecular-weigh dextran (DEX; mild inhibitor of fibrin formation and polymerization and von Willebrand factor-platelet interaction), aspirin (ASA; cyclooxygenase inhibitor), and prostaglandin E1 (PGE1; adenylate cyclase stimulator) to inhibit platelet adhesion on PE-100 was tested with this model. PE-100 segments were perfused with citrated human blood (5 ml, hematocrit, 35% +/- 5%) containing 6D1-treated, 111indium (111In-)labeled platelets (2.0 +/- 0.5 x 10(5) platelets/microliters) in a customized perfusion chamber (37 degrees C; flow, 1.2 ml/min; shear, 312 s-1). After a buffer flush under the same conditions, platelet deposition was measured by 111In-scintigraphy of the perfused conduits.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The inability of low-molecular-weight dextran, aspirin, and prostaglandin E1 to inhibit monolayer platelet adhesion to polyethylene. 768 20

We have investigated signaling (cAMP) and anabolic responses (mineralization of extracellular matrix [ECM]) to parathyroid hormone (PTH) in long-term (30 days) cultures of MC3T3-E1 cells, a murine model of osteoblast differentiation. Expression of PTH/PTH-related peptide receptor (PTH1R) mRNA is detected early and remains relatively constant for 2 weeks with somewhat higher levels observed during the second half of the culture period. In contrast to the relatively stable PTH1R mRNA expression, the cAMP response to PTH varies markedly with no response at day 5 and a marked response (80-fold versus control) by day 10. Responsiveness to PTH remains elevated with fluctuations of 30- to 80-fold stimulation throughout the remainder of the culture period. The timing and duration of PTH treatment to achieve in vitro mineralization of ECM was evaluated. When continuous PTH treatment was initiated before day 20, mineralization decreased. If continuous PTH treatment began on or after day 20, mineralization was unaffected. However, if treatment began on day 20 and then stopped on day 25, mineralization on day 30 was increased 5-fold. This mineralization response to intermittent PTH was confirmed in primary cultures of murine and human osteoblastic cells. These data provide a potential basis for understanding the differential responses to PTH (anabolic versus catabolic) and indicate the developmental temporal variance of anabolic and catabolic responses. Since cAMP signaling was relatively unchanged during this interval (day 10-30) and stimulation of adenylate cyclase only partially mimicked the PTH effect on increased mineralization, other signaling pathways are likely to be involved in order to determine the specific anabolic response to short-term PTH treatment during the differentiation process.
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PMID:Anabolic or catabolic responses of MC3T3-E1 osteoblastic cells to parathyroid hormone depend on time and duration of treatment. 1046 78

Aspirin is known to suppress platelet function markedly. However, aspirin at concentrations higher than 1 mM was observed to augment 1.3 microM U46619 (a stable thromboxane receptor (TP receptor) agonist) induced human platelet aggregation in this study. Moreover, at a concentration as low as 250 microM aspirin increased the aggregation induced by U46619 in 13% of normal and healthy individuals. The degree of platelet aggregation and the amount of ATP release were enhanced in U46619 stimulated platelet rich plasma by the addition of aspirin (>250 microM). U46619 was previously reported to inhibit forskolin-stimulated adenyl cyclase and to reduce the cAMP formation. Both of the augmentation effects of aspirin on U46619-induced aggregation and ATP release were blocked by MeSAMP, a P2Y(12) receptor antagonist. U46619 induced aggregation was suppressed by the addition of ADP scavenger (CP/CPK) with no significant change on ATP measured and the effect of CP/CPK could not be reversed by aspirin. In addition, aspirin augmented the inhibitory effect of U46619 on the cAMP production. Our present results suggested that the potentiation effect of aspirin on U46619 induced aggregation was related with the secreted ADP and the subsequent P2Y(12)/Gi related signaling.
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PMID:Augmentation of U46619 induced human platelet aggregation by aspirin. 1923 53

Prostaglandin F(2alpha) (PGF(2alpha)) and interleukin-1beta (IL-1beta) levels are elevated in inflamed dental pulp. The roles of IL-1beta and PGF(2alpha) in the pathogenesis of pulpal inflammation await investigation. We found that IL-1beta stimulated PGF(2alpha) production of human dental pulp cells. IL-1beta and PGF(2alpha) (0.5-10 mumol/L) also induced IL-8 production and mRNA expression in pulp cells. Aspirin inhibited IL-1beta-induced PGF(2alpha), but not IL-8 production. PGF(2alpha)-induced IL-8 production and mRNA expression were inhibited by U0126 (an inhibitor of mitogen-activated protein kinase kinase [MEK1/2]) inhibitor), whereas SQ22536 (an adenylate cyclase inhibitor) enhanced this event. These results indicate that IL-1beta-induced IL-8 production in pulp cells is not mainly via direct activation of cyclooxygenase and PGF(2alpha) generation. PGF(2alpha)-induced IL-8 production is possibly via activation of MEK/extracellular signal-regulated kinase signaling, but not by activation of adenylate cyclase. IL-1beta and PGF(2alpha) might involve the pathogenesis of pulpal inflammation via induction of IL-8 production.
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PMID:Prostaglandin F(2alpha)-induced interleukin-8 production in human dental pulp cells is associated with MEK/ERK signaling. 1934 95


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