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)

1. Adenylate cyclase (EC 4.6.1.1) activity has been determined in the parotid and sublingual glands of the mouse. Optimal activity of the enzyme was obtained at a Mg2+-concentration of 8 mM at pH 8.2, using AMP-PNP as the substrate. 2. Cyclic AMP degradation during the adenylate cyclase assay was relatively high in both the homogenate and the 40,000 g pellet-fraction of the glands. Theophylline was effective in inhibiting this degradation only in the parotid hemogenate, whereas isobutylmethylxanthine inhibited the cyclic AMP degradation in both salivary glands. Using the latter phosphodiesterase inhibitor, we observed a higher adenylate cyclase activity in the sublingual glands than in the parotid glands. 3. Various receptor-selective sympathetic and parasympathetic agonists and antagonists have been tested for their capacity to influence the adenylate cyclase activity and the glycoprotein secretion in the parotid and sublingual glands of the mouse, in vitro. (a) The parotid glycoprotein secretion was increased by beta-adrenergic agonists, which stimulate adenylate cyclase, and by cholinergic muscarinic drugs, which do not activate this enzyme. The adrenergic alpha-agonist phenylephrine appeared to be involved neither in the glycoprotein secretion nor in the direct regulation of the adenylate cyclase activity. (b) The sublingual protein and mucin secretion was increased by cholinergic muscarinic agents. The over-all protein secretion was stimulated also by phenylephrine, but this effect could be blocked by propranolol. The adenylate cyclase activity in membrane preparations was not stimulated by these secretogogues.
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PMID:Comparison of adenylate cyclase activity and in vitro secretion in the parotid and sublingual glands of the mouse. 3 65

A well-differentiated ductal adenocarcinoma of the Syrian golden hamster induced by N-nitrosobis(2-oxopropyl)amine was transplantable to both nude mice and inbred Syrian hamsters. The tumor grew rapidly in the nude mouse (12-fold increase in size at 45 days) in contrast to its growth in hamster (3-fold increase in size at 45 days). A curious finding associated with the slow-growing tumor in the hamster was an intense infiltration of the neoplasm by polymorphonuclear leukocytes unattended by either necrosis or infection. The neoplasm produced mucin and rapidly and specifically bound 125I-labeled secretin, although the degree of nonspecific binding (40.5%) was higher than that of control hamster pancreas (23%). Unstimulated adenyl cyclase activity (pmol cyclic adenosine 3':5'-monophosphate per mg protein) of the neoplasm was significantly higher [3.76 +/- 0.55 (S.E.)] than that of unstimulated normal hamster pancreas (1.03 +/- 0.44). Secretin did not significantly change the level of cyclic adenosine 3':5'-monophosphate (3.3 +/- 0.56) from the unstimulated level in the neoplasm, in contrast to its effect on normal pancreas where the level was increased 3-fold (3.1 +/- 0.75).
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PMID:Transplantable ductal adenocarcinoma of the Syrian hamster pancreas. 21 89

Treatment of rat submandibular acinar cell extracts with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) caused the dose-dependent activation of protein kinase C (PKC), assessed by the phosphorylation of a novel and highly specific substrate. This effect was duplicated by a diacylglycerol, but not by the 4 alpha-phorbol ester 4 alpha-phorbol 12,13-didecanoate. The TPA elevation of PKC was blocked by the PKC inhibitors H-7 and sangivamycin. In intact cells, TPA caused the translocation of PKC from cytosol to membrane, consistent with its known mode of activation. The beta-adrenergic agonist, isoproterenol, stimulated cAMP levels which were significantly reduced by preactivation of PKC. This inhibitory PKC effect was reversed by H-7. When cAMP was stimulated at the post-receptor level, however, by forskolin, NaF or GTP[gamma S], PKC did not inhibit, but rather enhanced the cyclic nucleotide response. Since PKC phosphorylated an endogenous protein of 55 kDa, the size of the beta 1 receptor, these findings indicate that, as in other cell types, PKC can desensitize adenylate cyclase by direct phosphorylation of the beta receptor, but potentiate the cAMP response by a post-receptor mechanism. In mucin secretion studies in the model, TPA alone caused the cAMP-independent release of up to 44% total mucin, which was much less than additive with the isoproterenol response. When the cAMP-mucosecretory response was stimulated at the adenylate cyclase level by forskolin, however, the TPA + forskolin effects were additive. These findings on the modulation of cAMP by PKC indicate cross-talk regulation in the phosphoinositide-cAMP signal transduction pathways in submandibular acinar cells.
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PMID:Regulation of the cAMP signal transduction pathway by protein kinase C in rat submandibular cells. 132 9

Key components of the mucous gel include the glycoprotein mucin and surface-active phospholipids. In the present study, mucin production and release of the surface-active phospholipid phosphatidylcholine (PC) into the medium were measured with an isolated canine mucous cell culture system. Stimulation of glycoprotein synthesis in response to 10(-4) mol/L histamine (160% +/- 9% of control, P < 0.01), 10(-6) mol/L gastrin (129% +/- 7%, P < 0.01), and 10(-6) mol/L carbamylcholine (129% +/- 7%, P < 0.01) was observed by metabolic labeling, whereas prostaglandin E2 (PGE2) had no effect. The effect of histamine was blocked by the H2 receptor antagonist cimetidine but not the H1 receptor antagonist diphenhydramine (P < 0.01). Activators of adenylate cyclase and cyclic adenosine monophosphate analogs significantly stimulated mucin synthesis (P < 0.05). A 7.8% +/- 1.7% increase in mucin above basal levels after 24 hours was observed with a solid-phase immunoassay in control wells, whereas histamine, gastrin, and carbamylcholine increased total mucin by 14% +/- 0.7%, 17% +/- 4.3%, and 20.4% +/- 4%, respectively (all P < 0.01), and PGE2 had no significant effect. PC release was stimulated by the administration of histamine, carbamylcholine, gastrin (108%-110% of control, P < or = 0.05), and PGE2 (120% of control, P < 0.01). The acid secretagogues histamine, gastrin, and carbamylcholine stimulated mucin synthesis and PC release. PGE2 has no direct role in the synthesis of canine gastric mucin but stimulates release of surface-active phospholipids. The mechanisms responsible for acid secretion provide for the coordinated production of the primary layer of defense against the injurious effects of low pH.
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PMID:Regulation of canine gastric mucin synthesis and phospholipid secretion by acid secretagogues. 850 Jul 55

Exposure of the intestinal mucosa to Vibrio cholerae enterotoxin (CT) results in mucus secretion from intestinal goblet cells. On the other hand, there is evidence that elevation of intracellular adenosine 3',5'-cyclic monophosphate levels is not sufficient to induce rapid mucin secretion. To determine whether CT has direct effects on human goblet cells and whether CT alone can elicit rapid exocytosis of apical mucin granules, purified CT was applied to monolayer cultures of well-differentiated HT-29-18 N2 cells, a goblet cell subclone derived from the human colon carcinoma line HT-29. CT bound with high affinity (dissociation constant = 10.5 +/- 1.9 nM) to receptors on these cells (approximately 60,000/apical membrane). Binding of radiolabeled CT was inhibited by excess CT or B subunit but not by A subunit. Preincubation of goblet cells with CT blocked the subsequent CT-specific ribosylation of a 45-kDa protein in membrane fractions of the cells and increased the activity of adenylate cyclase by 2- and 10-fold after 1 and 20 h, respectively. Light micrographs revealed that goblet cells incubated with CT, like control cells, contained abundant apical mucin granules. In contrast, goblet cells incubated with Ca2+ inophore A23187 and phorbol ester were rapidly depleted of mucin granules. Thus CT has direct physiological effects on HT-29 goblet cells, but these do not lead to rapid mucin secretion. These results raise the possibility that CT may accelerate mucin secretion in intact mucosa by an indirect mechanism perhaps mediated by mucosal nerves or other cell types.
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PMID:Interaction of cholera toxin with cloned human goblet cells in monolayer culture. 215 22

Release of [14C]glucosamine-labelled mucins was studied in vitro using well-characterised preparations of rat submandibular acini. Mucin release was stimulated by forskolin, an activator of the catalytic subunit of adenylate cyclase, and 3-isobutyl-1-methylxanthine (IBMX), a cyclic nucleotide phosphodiesterase inhibitor. Both stimulated in a dose-dependent manner to the same maximum as that seen with isoproterenol. Neither forskolin nor IBMX added in the presence of isoproterenol increased secretion above the maximum in response to isoproterenol alone, suggesting a similar mechanism of action, mediated by cyclic AMP. Prior exposure of acini to isoproterenol (10 microM) for 45 min, followed by washout resulted in (a) persistent increase in basal secretion which was abolished by propranolol and (b) reduced stimulation of mucin secretion in response to either a second isoproterenol challenge, noradrenaline or forskolin. Thus, exposure of rat submandibular acini in vitro desensitizes the cells to subsequent stimulation. Although this mimics the decreased beta-adrenergic secretory responses seen in submandibular cells from cystic fibrosis patients, results suggest that the isoproterenol-induced desensitization is at the level of beta-receptor and adenylate cyclase, rather than distal to cyclic AMP.
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PMID:Isoproterenol-induced desensitization of mucin release in isolated rat submandibular acini. 245 89

A polarized human clonal intestinal cell line exhibiting mucus secretion (Cl.16E) was used to study the expression and function of vasoactive intestinal peptide (VIP) receptors in mucus-secreting cells. Cl.16E cells expressed one class of receptors with a KD of 0.13 nM and a capacity of 67 fmol/mg protein. Covalent labeling of receptors followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a receptor protein with a Mr of 63,000 in Cl.16E cells. VIP stimulated adenylate cyclase activity in membranes from Cl.16E cells with an ED50 of 0.06 nM. In conditions where carbachol stimulated mucin secretion from filter-grown Cl.16E cells, VIP, dibutyryl adenosine 3',5'-cyclic monophosphate (DbcAMP), or forskolin did not alter basal secretion. However, VIP strongly potentiated carbachol-induced mucin secretion, since carbachol alone and VIP plus carbachol induced a 1.6- and 3.6-fold increase of mucin secretion above basal, respectively. This potentiating effect of VIP was mimicked by DbcAMP or forskolin. It was observed for VIP concentrations in the 0.1-100 nM range (ED50, 2 nM). VIP elicited a dramatic increase of intracellular cAMP levels in filter-grown Cl.16E cells with a dose-response curve (ED50, 4 nM) very similar to that observed for the modulation of mucin secretion. These studies suggest that the clonal cell line Cl.16E may be an invaluable cellular model for evaluating the neurohormonal control of mucus secretion.
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PMID:Functional VIP receptors in the human mucus-secreting colonic epithelial cell line CL.16E. 253 74

Purified cholera enterotoxin (20-50 micrograms) and dialyzed cholera filtrate (50-125 mg) increased net glycoprotein synthetic and secretory rates in rat intestinal epithelium. Specific goblet cell mucin secretion was increased 5- to 10-fold. However, other agents that increase intestinal cAMP and accelerate glycoprotein synthesis did not enhance mucin secretion. This was true for dibutyryl cAMP (10(-3) and 10(-2) M) with or without theophylline (10(-3) M) and isoproterenol (10(-4) M) with or without dibutyryl cAMP (10(-3) M). Hyperosmotic mannitol (450 mosmol/l), which increases fluid secretion but does not affect cAMP, and vasoactive intestinal peptide (2 X 10(-7) M), which increases both fluid secretion and cAMP, both failed to increase mucin secretion, implying that fluid "washout" of mucin adherent to the mucosal surface is not responsible for cholera-induced mucin secretion. Cycloheximide, an inhibitor of cholera diarrhea in vivo (20 mg/kg) or in vitro (1 mM), effectively abolished [3H]leucine incorporation into protein but did not affect cholera-induced mucin secretion. Colchicine (10-50 mg/kg) given to block microtubule assembly was similarly without effect on mucin secretion. These findings suggest that there is a dissociation of electrolyte/fluid and mucin secretory processes and cast doubt on the widely accepted notion that all cholera effects are mediated via the well-known adenylate cyclase-cAMP mechanism.
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PMID:Cholera-induced mucin secretion from rat intestine: lack of effect of cAMP, cycloheximide, VIP, and colchicine. 608 74

Short-term treatment of rat submandibular tissues with 10 microM isoproterenol (IPR) resulted in reduction of mucin secretion in response to the agonist during further incubation, and in increases in EC50 values. This IPR-induced reduction of secretion was coupled with selective decreases in the number of beta-adrenoceptors in the tissues and in their affinity for agonists, as assessed by measurement of the specific binding of [3H]dihydroalprenolol. Treatment of the tissues with IPR caused a 30% decrease in IPR-stimulated adenylate cyclase activity and a 25% increase in the GTP binding capacity of inhibitory G proteins (Gi proteins). This IPR treatment triggered a 60% increase in the ability of pertussis toxin (IAP) to catalyze ADP-ribosylation of Gi proteins in the tissue membranes. Enhanced function of stimulatory G proteins (Gs proteins) was observed only during the first incubation of the tissues with IPR. The IAP-catalyzed ADP-ribosylation of Gi proteins in tissues treated with IPR was decreased by prior treatment with cyclic AMP dependent protein kinase, but was increased markedly by prior treatment with alkaline phosphatase. Neither IPR-induced desensitization of protein secretion nor increase in the IAP-catalyzed ADP-ribosylation of Gi proteins was observed in the tissues pretreated with 0.25 microM okadaic acid. These findings suggest that the regulation of Gi protein phosphorylation plays an important role in the IPR-induced heterologous desensitization of mucin secretion from rat submandibular glands.
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PMID:Mechanism of isoproterenol-induced heterologous desensitization of mucin secretion from rat submandibular glands. Regulation of phosphorylation of Gi proteins controls the cell response to the subsequent stimulation. 769 46

Nd2 antibody recognizes an antigen that is tumor specific in pancreas. It has been used successfully in clinical radioimmunodetection studies to identify exocrine pancreatic tumors. In the present study we show that the uptake of radiolabeled Nd2 antibody by SW1990 pancreatic carcinoma cells was increased by the adenyl cyclase activator, forskolin. Dibutyryl cyclic AMP and forskolin were both effective in increasing the level of Nd2 antigen in SW1990 cells. Immunoprecipitation studies showed that the Nd2 epitope is associated with MUC1 mucin. Forskolin increased Nd2/MUC1 antigen in both a membrane fraction and a high buoyant density mucin-like fraction. Nd2 immunoreactivity was reduced by treatment of mucins with proteases and beta-mercaptoethanol. Immunohistochemical studies showed that periodate catalyzed beta-elimination greatly reduced Nd2 immunoreactivity. These results suggest that the Nd2 epitope is unusual in having characteristics of both a peptide and a carbohydrate, protease and conformation sensitivities and involvement of O-linked oligosaccharides. Nd2 antibody does not react with several known pancreatic cancer antigens. In summary, activation of the cyclic AMP pathway increased cellular uptake of Nd2 antibody and the cellular expression of the tumor-specific, mucin-associated Nd2 antigen. These results suggest a means of improving the effectiveness of monoclonal antibodies in targeting tumor antigens for the diagnosis and treatment of malignancy.
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PMID:Forskolin increases the expression of the pancreatic tumor antigen, Nd2, and uptake of Nd2 antibody. 1102 87


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