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)

Many cells develop enhanced adenylate cyclase activity after prolonged exposure to drugs that acutely inhibit the enzyme and it has been suggested that this adaptation may be due to an increase in Gs alpha. We have treated wild-type and Gs alpha-deficient cyc- S49 mouse lymphoma cells with a stable analogue (SMS 201-995) of the inhibitory agonist somatostatin. After incubation with SMS for 24 h, the forskolin-stimulated cAMP synthetic rate in intact cyc- cells was increased by 76%, similar to the increase found in the wild-type cells. Forskolin-stimulated adenylate cyclase activity in the presence of Mn2+ was also increased in membranes prepared from SMS-treated cyc- cells; however, guanine nucleotide-mediated inhibition of adenylate cyclase activity was not changed despite a small decrease in inhibitory Gi alpha subunits detected by immunoblotting. Pretreatment of cyc- cells with pertussis toxin prevented SMS from inducing the enhancement of forskolin-stimulated cAMP accumulation in intact cells. After chronic incubation of cyc- cells with SMS, exposure to N-ethylmaleimide, which abolished receptor-mediated inhibition of cAMP accumulation, did not attenuate the enhanced rate of forskolin-stimulated cAMP synthesis compared to N-ethylmaleimide-treated controls. These results with cyc- cells demonstrate that an adaptive increase in adenylate cyclase activity induced by chronic treatment with an inhibitory drug can occur in the absence of expression of Gs alpha.
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PMID:Prolonged activation of inhibitory somatostatin receptors increases adenylate cyclase activity in wild-type and Gs alpha-deficient (cyc-) S49 mouse lymphoma cells. 132 4

We have reported that prostaglandin E2 (PGE2) is a selective stimulator of the antigen-specific IgE response [6]. Because PGE2 is known to elevate intracellular cAMP, we investigated the regulatory role of cAMP in the production of antigen-specific IgE. Anti-TNP IgE response was induced by stimulating TNP-KLH-primed BALB/c spleen cells with the same antigen in vitro. Addition of 10-100 microM dibutyryl cAMP (DBcAMP) to the lymphocyte culture resulted in a 2-3-fold increase in anti-TNP IgE response without affecting the production of anti-TNP IgG1 or IgM. Forskolin, a stimulator of adenylate cyclase, also specifically augmented the IgE response. In contrast, 2',5'-dideoxyadenosine, an inhibitor of adenylate cyclase, suppressed IgE production in an isotype-specific manner. These results suggest that IgE synthesis can be selectively modulated by intracellular cAMP level. Enhancement of IgE production by DBcAMP was observed, particularly in highly primed spleen cells, suggesting that IgE-committed B cells are subjected to regulation by cAMP.
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PMID:Selective regulation of antigen-specific IgE response by cyclic AMP level in murine lymphocytes. 133 Sep 1

Phorbol-myristate-acetate (PMA) induced in lymphocytes the production or reactive oxygen intermediates in a process which was stimulated by the presence of vasoactive intestinal peptide (VIP) in a dose-dependent response at VIP concentrations in the range 10(-11)-10(-8) M. The dissociation constant for the high-affinity receptors of VIP agreed with the ID50 of the activation of adenylate cyclase, and the ID50 for the stimulation by VIP of PMA-induced chemiluminescence, which were close to 0.2 nM VIP. Forskolin produced in lymphocytes an effect quite similar to VIP. A comparison of the response to VIP and forskolin of lymphocytes and monocytes showed that, in contrast to forskolin, VIP failed to induce the above described effect in monocytes. A possible mechanism involving protein kinase C, which is activated by PMA, and an intracellular signal linked to VIP receptors is pointed out. This study further supports a role for VIP as a mediator in the neuroimmune system.
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PMID:Vasoactive intestinal peptide enhances phorbol myristate acetate-induced chemiluminescence in human lymphocytes. 133 43

A number of regulatory peptides were investigated for their ability to elevate plasma cAMP. Pituitary adenylate cyclase activating peptide (PACAP)-27, PACAP-38, helodermin, helospectin I and II, vasoactive intestinal peptide (VIP), glucagon, parathyroid hormone (PTH), calcitonin and calcitonin gene-related peptide were among the peptides that were highly effective in raising plasma cAMP when given intravenously in equimolar doses to conscious mice. PACAP-27 and -38 were more effective than any of the other peptides. PACAP 16-38, secretin, gastrin-17, galanin, somatostatin, cholecystokinin-8s, pancreatic polypeptide, substance P, peptide YY and neuropeptide Y were inactive and also did not interfere with the PACAP-27-evoked rise in plasma cAMP levels. Repeated injections of PACAP-27 every 30 min caused a progressive reduction in the plasma cAMP response (measured 5 min after each injection). Forskolin, an activator of adenylate cyclase, dose-dependently raised the plasma concentration of cAMP and displayed a synergistic effect when given in a low dose concurrently with PTH or PACAP-38. The phosphodiesterase inhibitor rolipram dose-dependently raised the plasma concentration of cAMP. Combined treatment with PACAP-27 and a threshold dose of rolipram resulted in an exaggerated plasma cAMP response. Kidney hilus ligation suppressed the responses to PACAP-38, PTH, helodermin, helospectin, VIP, glucagon and calcitonin. Hepatectomy suppressed the response to glucagon but was without effect on the response to the other peptides. Pancreatectomy and spleenectomy reduced the response to VIP, but was without effect on the response to the other peptides. PACAP-27 stimulated cAMP efflux from the isolated rat tail vein. Hence, it cannot be excluded that blood vessels contribute to the peptide evoked plasma cAMP response in vivo.
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PMID:Neuropeptides of the vasoactive intestinal peptide/helodermin/pituitary adenylate cyclase activating peptide family elevate plasma cAMP in mice: comparison with a range of other regulatory peptides. 133 41

Vasoactive intestinal peptide (VIP) evokes little or no secretion of catecholamines from cultured bovine chromaffin cells. However, pretreatment of chromaffin cells with pertussis toxin (PTX, 100 ng/ml for > or = 4 h) revealed that VIP is a secretagogue. In PTX-treated cells catecholamine secretion evoked by VIP occurs with minimal elevation of cyclic AMP and is only slightly enhanced by cyclic nucleotide phosphodiesterase inhibitors. Forskolin, a direct activator of adenylate cyclase, causes delayed secretion of catecholamines from chromaffin cells treated with PTX, but only with pronounced elevation of cyclic AMP levels. Stimulation of catecholamine secretion by histamine, known to activate phosphatidylinositol-specific phospholipase C in chromaffin cells, is also enhanced by preincubation of the cells with PTX. These results suggest that in the bovine chromaffin cell a PTX-sensitive G-protein mediates tonic inhibition of secretion, possibly by preventing activation of phospholipase C.
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PMID:Vasoactive intestinal peptide is a secretagogue in bovine chromaffin cells pretreated with pertussis toxin. 133 35

Ketoconazole is an imidazole derivative used as an antimycotic agent with reported effects on the endocrine system, but very little is known about its possible actions on thyroid function. Our purpose was to study the influence of this substance on the basal and TSH-stimulated iodide uptake in the rat thyroid cell strain FRTL-5. Ketoconazole (1-50 mumol/l) was shown to slightly increase the basal iodide uptake but, at higher concentrations (75-100 mumol/l), it sharply decreased iodide uptake below the basal levels. When the cells were cultured under bTSH stimulation (30 UI/l), the inhibitory effect of ketoconazole was exerted at concentrations as low as 25 mumol/l. This inhibition was observed even if it was added to the culture medium immediately before the Na125I addition. Forskolin, a stimulator of adenylate cyclase activity, was unable to prevent the iodide uptake inhibition. Low doses of ketoconazole increased cAMP concentrations. In the presence of TSH this effect was more evident in an inverse dose-dependent way. Because of its dual action, it can be assumed that ketoconazole could influence the iodide uptake in the FRTL-5 cells through more than one mechanism.
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PMID:Effects of ketoconazole on the iodide uptake by FRTL-5 cells. 133 1

Electrical field stimulation (EFS) of nerves intrinsic to the opossum lower esophageal sphincter (LES) produces LES relaxation, an increase in its guanosine 3',5'-cyclic monophosphate (cGMP) content, and hyperpolarization of its circular muscle membrane potential difference. Activation of esophageal nerves produces an analogous hyperpolarization of the circular esophageal smooth muscle. These studies test the hypothesis that cGMP is an intracellular mediator of this hyperpolarization. The transmembrane potential difference of circular smooth muscle cells was recorded with glass microelectrodes. Nerve-mediated smooth muscle hyperpolarization was evoked by EFS (1 ms, 50 V pulses). Forskolin, an activator of adenylate cyclase, and sodium nitroprusside, an activator of guanylate cyclase, produced hyperpolarization. Cystamine and methylene blue, inhibitors of guanylate cyclase, blocked the hyperpolarization elicited by sodium nitroprusside, but not that by forskolin. Both also reversibly abolished the hyperpolarization evoked by EFS. Membrane-permeable derivatives of cGMP produced a concentration-dependent hyperpolarization. These data support the hypothesis that cGMP is an intracellular mediator of nerve-induced esophageal smooth muscle hyperpolarization.
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PMID:Guanylate cyclase inhibitors: effect on inhibitory junction potentials in esophageal smooth muscle. 135 3

Using rat hepatocytes we confirmed our previous results that glucagon and beta-adrenergic agonists increased the enzyme activity of alanine aminotransferase (AAT) and propranolol abolished their effects. Only the enzyme activity was measured and other parameters like quantity of the enzyme or activation due to modification were not looked for. As in perfusion experiment phenylephrine and phenoxybenzamine (alpha-agonist and alpha-antagonist respectively) also alpha-antagonist respectively) also increased the AAT activity in isolated rat hepatocytes and propranolol reversed these effects. The additive effect of glucagon and phenoxybenzamine on AAT was also persistent in hepatocyte system. Fructose-1:6-bisphosphatase (Fru-P2-ase), another key enzyme in gluconeogenic pathway, was elevated by glucagon and other beta-adrenergic agonists both in liver perfusion and isolated hepatocyte experiments and was brought back to the normal level by propranolol. In this case also only the enzyme activity was measured and no other parameters were looked for. Unlike AAT this enzyme was not stimulated by phenylephrine or phenoxybenzamine. But AAT and Fru-P2-ase activities were increased significantly by adenylate cyclase activators like fluoride or forskolin. Thus, it appears that the regulation of fru-P2-ase by glucagon is purely a b-receptor mediated process whereas AAT activation shows a mixed type of regulation where some well known alpha-agonist and antagonists are behaving as beta-agonists. Results further indicate the presence of phosphodiesterase in hepatocyte membrane which was stimulated by glucagon and brought back to the normal level by propranolol. The different adrenergic compounds stated above, not only modified the activity of the above two enzymes but also stimulated glucose production by hepatocytes from alanine which was in turn abolished by propranolol as well as amino oxyacetate (AOA), a highly specified inhibitor of AAT. This confirm the participation of AAT in gluconeogenesis from alanine in liver. Forskolin and fluoride also increased the glucose production from alanine and showed additive effects with glucagon, phenylephrine and phenoxybenzamine.
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PMID:Effect of adrenergic agonists and antagonists on alanine amino transferase, fructose-1:6-bisphosphatase and glucose production in hepatocytes. 135 93

1. Cultured iridophores from the freshwater goby, Odontobutis obscura, were used to investigate adrenergic mechanisms of movement of platelets in the iridophores. 2. Norepinephrine, which was assumed to be the transmitter of the iridophore nerves, induced dispersion of platelets within the cells. 3. The effect of norepinephrine was inhibited by an alpha-adrenergic antagonist, yohimbine, but not by a beta-adrenergic antagonist, propranolol. 4. Isoproterenol, a beta-adrenergic agonist, failed to bring about aggregation of platelets. 5. Forskolin, an activator of adenylate cyclase, was effective in inducing aggregation of platelets. 6. 8-Br-cAMP caused the aggregation of platelets and inhibited the norepinephrine-induced dispersion of platelets. 7. It appears that the adrenoceptors of the iridophores of this species are solely of the alpha type; they mediate the dispersion of platelets; and an increase in intracellular levels of cAMP induces the aggregation of platelets.
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PMID:Adrenergic mechanisms associated with the movement of platelets in iridophores from the freshwater goby, Odontobutis obscura. 135 36

Oxyntomodulin (OXM), a glucagon-containing peptide extended at its C-terminal end by an octapeptide, is a potent inhibitor of gastric acid secretion in rat and man. OXM appears to act on gastric mucosa at least partially through a stimulation of gastric somatostatin release. We have investigated the effects of OXM on a somatostatin-secreting cell line (RIN T3) derived from a radiation-induced rat insulinoma and characterized specific binding sites for this peptide. OXM increased somatostatin release with an ED50 of 2.3 nM. OXM also stimulated the cAMP accumulation in intact RIN T3 cells and adenylate cyclase activity in RIN T3 cell membranes with ED50 values of 0.5 and 11 nM, respectively. On these parameters, glucagon was 10-30 times less potent than OXM. Forskolin, isobutylmethylxanthine, and 8-bromo-cAMP mimicked the effect of OXM on somatostatin release. Specific binding for mono-[125I]OXM was dependent upon time and membrane concentration. Binding of mono-[125I]OXM was inhibited by OXM and glucagon in a concentration-dependent manner, with dissociation constants (Kd) of 4.5 and 43 nM, respectively. The nonhydrolyzable analogs of GTP (guanosine 5',3-O-(thio)triphosphate and guanosine 5' (beta,gamma-imino)triphosphate decreased the binding of mono-[125I]OXM to its binding sites. Covalent cross-linking of mono-[125I]OXM or mono-[125I]glucagon to RIN T3 cell membranes followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated a single radiolabeled band at 63,000 mol wt, which differed from that observed after cross-linking with liver plasma membranes (55,000 mol wt). These results demonstrate the presence of specific high affinity binding sites for OXM in a somatostatin-secreting cell line (RIN T3) and their coupling to adenylate cyclase via guanine nucleotide-binding proteins.
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PMID:Characterization of binding sites for oxyntomodulin on a somatostatin-secreting cell line (RIN T3). 137 46


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