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)

Cloned Lewis lung carcinoma (LLC) variants were used in an in vitro migration model for dissemination, to determine if prostaglandin E2 (PGE2) produced by nonmetastatic LLC cells could directly stimulate dissemination of metastatic LLC cells and to identify an intracellular mechanism for such an effect. The migration of metastatic LLC clones was stimulated not only by exogenous PGE2 but also by nonmetastatic LLC cells, by their production of a migration-stimulatory factor which was sensitive to indomethacin and anti-PGE2 antibodies. Nonmetastatic LLC clones were unresponsive to migration stimulation by PGE2. The results of in vivo metastasis studies were consistent with those of in vitro migration studies. In vivo lung metastasis was increased by PGE2, as well as by nonmetastatic cells when they were either admixed with the metastatic LLC inoculum, irradiated and injected adjacent to the metastatic LLC tumor, or localized in chambers and implanted s.c. into mice given injections of metastatic LLC cells. Indomethacin blocked metastasis stimulation by nonmetastatic cells. The in vitro PGE2 stimulation of metastatic LLC cells appeared to be linked to a cyclic AMP (cAMP) response, since migration could also be stimulated by dibutyryl-cyclic AMP and blockage of a cAMP response with nicotinic acid ablated the PGE2 stimulation of migration. In vivo metastasis could be stimulated by elevation of cAMP with aminophylline. The differential responsiveness of metastatic versus nonmetastatic LLC cells to PGE2 could not be due to PGE2-adenylate cyclase coupling, since PGE2 increased the cAMP levels in cultures of both metastatic and nonmetastatic LLC cells. There was, however, a difference in the cyclic AMP-dependent protein kinase (PKA) response to PGE2, with PKA activity of metastatic LLC being stimulated by PGE2 and by the adenylate cyclase-stimulator forskolin, whereas PKA of nonmetastatic LLC was not stimulated by these cAMP elevators, suggesting a dysfunction in the cAMP-PKA coupling.
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PMID:Association of a functional prostaglandin E2-protein kinase A coupling with responsiveness of metastatic Lewis lung carcinoma variants to prostaglandin E2 and to prostaglandin E2-producing nonmetastatic Lewis lung carcinoma variants. 215 67

Bombesin is a potent mitogen for Swiss 3T3 cells and can stimulate DNA synthesis in the absence of any other growth factor. This effect is mediated by multiple synergistic signaling pathways, including an accumulation of intracellular cyclic AMP (cAMP) and an increase in c-fos mRNA expression. The cyclooxygenase inhibitor indomethacin abolished prostaglandin E2 release and substantially depressed cAMP levels induced by bombesin (EC50 congruent to 10 nM). In contrast, indomethacin at 1 microM did not affect 80K phosphorylation or Ca2+ mobilization by bombesin, indicating that cAMP synthesis can occur through a phospholipase C-independent pathway. Indomethacin caused a 30 to 35% decrease in c-fos induction and DNA synthesis in cells treated with bombesin (EC50 congruent to 40 nM). Significantly, the inhibitory effect of indomethacin was reversed in the presence of forskolin, a direct activator of adenylate cyclase. We conclude that cAMP plays a regulatory role in c-fos induction and mitogenesis in Swiss 3T3 cells treated with bombesin.
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PMID:Bombesin stimulation of c-fos expression and mitogenesis in Swiss 3T3 cells: the role of prostaglandin E2-mediated cyclic AMP accumulation. 217 Jan 55

Histamine stimulated large increases of cyclic adenosine monophosphate (cAMP) in freshly isolated human blood monocytes in the presence of R02-1724, a specific cAMP phosphodiesterase inhibitor. This was mediated by H2 receptors, since it was inhibited by cimetidine but not chlorpheniramine. Stimulation was attenuated in cells aged in culture 1-2 days. Indomethacin prevented the desensitization, suggesting that a cyclooxygenase product was responsible. Desensitization was heterologous, since the adenylate cyclase responses to 5'-(N-ethylcarboxamido)adenosine (A2 receptor agonist), isoproterenol (beta-adrenoceptor agonist), and prostaglandin E2 (PGE2) also declined during culture. The loss of sensitivity to histamine was restored by incubating monocytes with PGE2 in the presence of indomethacin. The results indicate that, while PGE2 inhibits monocyte functions via cAMP, its accumulation paradoxically permits cells to escape this regulation through a heterologous desensitization of the cAMP response to itself and other agonists.
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PMID:Prostaglandin-dependent desensitization of human monocyte cAMP responses. 217 33

Exposure to (-)-isoprenaline (25 microM, 1 h) caused a stereoselective, time and concentration-related decrease in smooth muscle beta 2-adrenoceptor function in guinea-pig trachea. Furthermore, tracheal relaxant responsiveness to the beta-adrenoceptor agonists (+/-)-fenoterol and (-)-noradrenaline was reduced, while that to theophylline and nitroprusside was unaffected. Responsiveness to forskolin was marginally but significantly reduced. Indomethacin, a cyclooxygenase inhibitor and mepacrine, an inhibitor of phospholipid turnover, had no significant effect on the extent of isoprenaline-induced desensitization. Conversely, cortisol (25 microM) significantly reduced desensitization and enhanced the rate of spontaneous recovery of responsiveness to isoprenaline. Desensitization was not accompanied by a reduction in the density of beta-adrenoceptors in the trachea, as assessed by binding and light microscopic autoradiography using [125I]iodocyanopindolol [( 125I]CYP). Thus, desensitization was probably caused primarily by beta-adrenoceptor/adenyl cyclase uncoupling. This model may be useful in investigations of the effect of glucocorticoids on the beta-adrenoceptor dysfunction recognized in severe asthma.
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PMID:Beta-adrenoceptor desensitization in guinea-pig isolated trachea. 285 13

The action of somatostatin (SS) on acid secretion and histamine release was studied in isolated gastric mucosa of toads mounted in Ussing chambers. SS inhibited H+ secretion and histamine release stimulated by cholinergic and gastrinergic secretagogues. Exogenous histamine stimulation of H+ secretion was blocked noncompetitively by SS in a dose-dependent manner. In mucosae maximally stimulated by histamine or forskolin and cimetidine, acetylcholine (ACh) and tetragastrin (TG) induced a direct stimulation of the oxyntopeptic cell not inhibited by SS. Indomethacin, an inhibitor of prostaglandin synthesis, did not prevent SS inhibition of histamine stimulation. Pretreatment with SS abolished forskolin stimulation of H+ secretion. SS induced a small inhibition of the stimulatory effect of N6, 2'-O-dibutyryladenosine 3',5'-cyclic monophosphate. These results suggest that SS inhibits acid secretion stimulated by secretagogues through different mechanisms: 1) inhibition of histamine release by ACh and TG, 2) inhibition of endogenous and exogenous histamine stimulation through a blockade of adenylate cyclase, and 3) an inhibitory effect subsequent to the synthesis of adenosine 3',5'-cyclic monophosphate. The direct activation of the oxyntopeptic cell by ACh and TG does not seem to be affected by somatostatin.
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PMID:Somatostatin inhibition of secretagogue and forskolin-stimulated gastric acid secretion. 289 87

A rapidly increasing scientific literature now supports the possibility of an alcohol-prostaglandin interaction. This chapter reviews evidence for both direct and indirect biochemical interactions between ethanol and the metabolism of arachidonic acid and several related compounds. Much of the present data is based on pharmacological manipulation of prostaglandin (PG) levels by potent nonsteroid anti-inflammatory agents such as indomethacin. Indomethacin markedly alters the behavioral response to ethanol, particularly in the mouse model. These data suggest that PGs are involved in the behavioral response to acute ethanol exposure in the mouse. In other animal models, alcohol has been reported to alter blood platelet metabolism of arachidonic acid, to suppress the enzymatic degradation of PGs, and to alter the response of the adenyl cyclase system to several hormones including PGs of the "E" series. In humans, both the stimulation and inhibition of PG synthesis is reported to aid the treatment of various aspects of alcoholism. Further, PGs are reported to protect against alcohol-induced fatty liver, and both PGs and arachidonic acid protect the gastric mucosa against ethanol-induced lesions. Certainly the residual consequences of acute, excessive ethanol consumption are commonly treated with a prostaglandin synthesis inhibitor. The material in this chapter is an attempt to review the data and to discuss the molecular mechanism underlying these observations.
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PMID:Biochemical interactions of ethanol with the arachidonic acid cascade. 298 78

5-Hydroxytryptamine (5-HT) has been claimed to mediate intestinal secretion in morphine withdrawal diarrhea through stimulation of local prostaglandin formation without involving cyclic adenosine monophosphate. Therefore, experiments were performed to study (a) the effects of exogenous 5-HT and the cyclic adenosine monophosphate-dependent secretagogue, vasoactive intestinal polypeptide, on intestinal prostaglandin E2 (PGE2) formation and (b) the involvement of calcium in the secretory response to close intraarterial infusion of 5-HT, PGE2, or vasoactive intestinal polypeptide in tied-off loops of rat jejunum in vivo. 5-Hydroxytryptamine and vasoactive intestinal polypeptide reversed fluid absorption to net secretion (p less than 0.01), but only 5-HT caused an increase in luminal PGE2 output (p less than 0.01). Indomethacin and d,l-verapamil prevented only the secretory effect of 5-HT. Exogenous PGE2 (1.6-160 ng/min) reversed absorption to secretion (p less than 0.01) in a dose-dependent manner, irrespective of whether the rats were pretreated with indomethacin or not. Racemic and l-verapamil, but not d-verapamil, markedly reduced (p less than 0.01) the secretory effect of physiologically low doses of PGE2 (1.6 and 16 ng/min), whereas high doses of PGE2 (160 ng/min), which caused a significant increase in mucosal cyclic adenosine monophosphate (p less than 0.005), were not inhibited by verapamil. These data suggest that PGE2 may be an important intermediate in the transduction mechanism leading to 5-HT-induced intestinal secretion, and that physiologic doses of PGE2 may act by facilitating calcium entry, rather than by increasing intracellular calcium through activation of the adenylate cyclase.
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PMID:Significance of calcium for the prostaglandin E2-mediated secretory response to 5-hydroxytryptamine in the small intestine of the rat in vivo. 300 62

Adenosine and prostaglandins (PGs) are known inhibitors of oxyntic cell function. Using quantitative cytochemistry of hydroxyl ion production (HIP) in guinea-pig oxyntic cells, we examined the effects of adenosine and PGs on secretagogue-stimulated HIP. Adenosine (10(-6) M) inhibited the actions of histamine (10(-14) M) and gastrin (2.5 X 10(-12) M) by 69 and 67%, respectively, but not that of dibutyryl cyclic AMP (10(-16) M) or carbachol (10(-9) M). These observations suggest that adenosine does not influence the Ca++-dependent pathway of carbachol action and that the adenosine activity precedes the generation of cyclic AMP. Adenosine and related analogs, N6-L-phenylisopropyladenosine and 5-N-ethylcarboxam-idoadenosine (10(-12) to 10(-14) M), inhibited histamine-stimulated HIP (10(-14) M) in the following order: N6-L-phenylisopropyladenosine greater than 5-N-ethylcarboxamidoadenosine greater than adenosin. The adenosine antagonist, 1,3-diethylphenylxanthine (10(-6) M), reversed the inhibitory effects of adenosine. Exogenous PGE2 (10(-6) M) also inhibited histamine- and gastrin-stimulated HIP by 65 and 55%, respectively. Indomethacin (10(-6) M) and flurbiprofen (10(-6) M), PG synthesis inhibitors, potentiated the action of histamine by 175 and 159%, respectively. Adenosine was incapable of reversing this potentiated effect. These data indicate that adenosine and related analogs are inhibitors of oxyntic cell HIP and suggest that these biological properties are mediated by binding to a cell surface receptor and thereby regulating oxyntic cell adenylate cyclase activity. The more potent properties of N6-L-phenylisopropyladenosine as compared to 5-N-ethylcarboxamidoadenosine are consistent with activity at the high-affinity surface adenosine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of guinea-pig oxyntic cell function by adenosine and prostaglandins. 300 79

TSH is a trophic factor for cultured rat thyroid cells (FRTL-5). In the present study we have investigated the mechanism by which TSH promotes cell growth and evaluated the possible role of the adenylate cyclase (AC)-cAMP system in this process. The mitogenic activity of several agents was evaluated by measuring their effect on cell number or 3H-thymidine incorporation into DNA. Forskolin and cholera toxin, two potent and specific activators of the AC, induced a dose dependent increase of 3H-thymidine incorporation. The maximal stimulation, observed at concentrations of 10 microM and 10 ng/ml, respectively, was beta 80% of that obtained with optimal concentrations of TSH. A similar effect was obtained with a Graves' IgG preparation (0.2 mg/ml) able to stimulate the thyroid AC or with 3-isobutyl-1-methyl-xanthine (IBMX, 0.5 mM), a phosphodiesterase inhibitor. 8-bromo cAMP (0.5 mM), a cAMP analog, also stimulated 3H-thymidine incorporation, and its potency was approximately 60% of that of TSH. Similar results were obtained when the mitogenic activity of these compounds was evaluated by cell number. Norepinephrine (NE, 10 microM), although devoid of AC stimulatory activity in these cells, also stimulated 3H-thymidine incorporation, but its potency was only 20-30% of that of TSH. Indomethacin (100 microM), an inhibitor of phospholipid and arachidonic acid metabolism, was able to inhibit the stimulatory effect of NE (84%), and to a lesser extent of TSH (63%) and cholera toxin, had minor effect on forskolin (24%), IBMX (16%) and Graves' IgG (8%), and no effect on 8-bromo cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of the adenylate cyclase-cAMP system on TSH-stimulated thyroid cell growth. 303 75

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


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