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. Comparison of the rank order of potency of the natural prostanoids prostaglandin E2 (PGE2), PGD2, PGF2 alpha and carbaprostacyclin in stimulating cyclic AMP in Jurkat cells is consistent with the presence of an EP receptor. 2. Lack of responsiveness to the EP1/EP3 selective agonist, sulprostone, and the EP2 agonists, butaprost and AH 13205, indicates that this receptor is not of the EP1, EP2 or EP3 subtypes. 3. Inhibition of PGE2-stimulated cyclic AMP by the EP4 antagonist, AH 23848 is non-competitive, unlike the competitive antagonism reported in the pig saphenous vein EP4 preparation. Furthermore, 16,16-dimethyl PGE2 is 100 fold less potent than PGE2 in Jurkat cells, while these agonists are equipotent in the rabbit jugular vein purported EP4 preparation. In addition, 1-OH PGE1, which also is active in the rabbit jugular vein preparation, is inactive in Jurkat cells at concentrations up to 1 x 10(-4) M. These data are not wholly consistent with any adenylate cyclase coupled EP receptor described to date. 4. It is postulated that an EP receptor, positively coupled to adenylate cyclase, with a unique pharmacological profile is present in Jurkat cells.
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PMID:An EP receptor with a novel pharmacological profile in the T-cell line Jurkat. 758 50

1. The aims of this study were to characterize the EP receptor subtype mediating the inhibition of superoxide anion generation by formyl methionyl leucine phenylalanine (FMLP)-stimulated human neutrophils, and to test the hypothesis that adenosine 3':5'-cyclic monophosphate (cyclic AMP) is the second messenger mediating the inhibition of the neutrophil by prostaglandin (PG)E2. 2. PGE2 (0.001-10 microM) inhibited FMLP (100 nM)-induced O2-generation from human peripheral blood neutrophils in a concentration-dependent manner, with an EC50 of 0.15 +/- 0.03 microM, and a maximum effect ranging from 36-84% (mean inhibition of 68.7 +/- 2.5%, n = 32). 3. The EP2-receptor agonists, misoprostol, 11-deoxy PGE1, AH13205 and butaprost, all at 10 microM, inhibited O2- generation, causing 95.5 +/- 2.9%, 56.8 +/- 5.2%, 37.1 +/- 6.6% and 18.9 +/- 4.4% inhibition respectively, the latter two being much less effective than PGE2. Similarly, the EP1-receptor agonist, 17-phenyl PGE2 (10 microM), and the EP3/EP1-receptor agonist, sulprostone (10 microM), also inhibited O2- generation, causing 32.2 +/- 7.0% and 15.3 +/- 3.4% inhibition respectively. 4. The non-selective phosphodiesterase inhibitor, isobutyl methylxanthine (IBMX, 0.25 mM) inhibited the FMLP response by 54.5 +/- 5.0%. In addition, IBMX shifted concentration-effect curves for PGE2, misoprostol, 11-deoxy PGE1, butaprost, and AH 13205 to the left, to give EC50s of 0.04 +/- 0.03 (n = 13), 0.07 +/- 0.03 (n = 4), 0.08 +/- 0.03 (n = 4), 0.33 +/- 0.13 (n = 4) and 0.41 +/- 0.2 microM (n = 3) respectively, allowing equieffective concentration-ratios (EECs, PGE2 = 1) of 11.5, 5.3, 50.7 and 12.7 to be calculated. This agrees well with the relative potencies of these agonists at EP2 receptors.5. By contrast, even in the presence of IBMX (0.25 mM), sulprostone and 17-phenyl PGE2 were only effective at the highest concentration (10 microM), and gave EECs of > 700 and 486 respectively, suggesting that EP1 or EP3 receptors are not involved.6. The selective type IV phosphodiesterase inhibitor, rolipram at 2 and 10 nM did not inhibit the FMLP response, but at the higher concentration of 50 nM, it decreased the FMLP response by 46.6 +/-7.3%.However, rolipram shifted concentration-effect curves for PGE2 to the left to give EC50s of 0.06 +/-0.022,0.015 +/- 0.0, 0.012 +/- 0.006 microM at 2, 10 and 50 nM respectively, compared to the control EC50 of0.27+/- 0.09 microM for PGE2.7. The EP4/TP receptor blocking drug, AH 23848B (10 microM, 10 min) did not inhibit 02- generation by PGE2, but was found to potentiate significantly the effect of PGE2 at the lower concentrations of PGE2 tested (0.001-0.1 microM).8. The adenylate cyclase inhibitor, SQ 22,536 (0.1 mM, 2 min) reduced PGE2-induced inhibition of 02-production, giving an EC50 in the absence of SQ 22,536 of 0.24 +/- 0.1, and 1.9 +/- 1.1 AM in its presence.9. These results suggest that inhibition of superoxide generation by PGE2 is mediated by stimulation ofEP2 receptors and activation of adenylate cyclase, leading to the elevation of intracellular levels of cyclic AMP.
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PMID:Characterization of the PGE receptor subtype mediating inhibition of superoxide production in human neutrophils. 760 49

A fourth PGE receptor subtype, the EP4 receptor, has recently been described in the pig saphenous vein (PSV). Similar to the EP2 receptor, it mediates relaxation and is linked to stimulation of adenylate cyclase. The aim of this study was to determine whether or not the EP receptor present in the rabbit jugular vein (RJV), currently classified as an atypical EP2 receptor, is of the EP4 subtype. The relaxant activities of four EP2 agonists, 11-deoxy PGE1, 16,16-dimethyl PGE2, butaprost, and AH 13205, on the RJV and PSV have been examined, and the effect of the EP4 receptor antagonist AH 23,848B studied. The EP2 agonists showed a similar order of potency on the two preparations. 11-Deoxy PGE1 and 16,16-dimethyl PGE2 were potent agonists on the EP4 receptors of the PSV and on the RJV giving approximately equi-effective concentration ratios (EECs) of 2.0-6.6 and 2.8-9.9, respectively, compared to PGE2 (EEC = 1), and so do not discriminate between EP2 and EP4 receptors. Butaprost was less active on these preparations (EEC 42-43) than on classical EP2 receptors, and AH 13205 was much less active (EEC 3100-2780). While these results suggest that the EP receptors on the RJV are of the EP4 subtype, this was not confirmed using the EP4 receptors antagonist AH 23,848B.
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PMID:Comparison of the EP receptor subtypes mediating relaxation of the rabbit jugular and pig saphenous veins. 766 4

We previously cloned a cDNA for a mouse PGE receptor positively coupled to adenylate cyclase from mouse mastocytoma cells, and reported it as EP2 subtype of PGE receptor [Honda, A., Sugimoto, Y., Namba, T., Watabe, A., Irie, A., Negishi, M., Narumiya, S. and Ichikawa, A. (1993) J. Biol. Chem. 268, 7759-7762]. However, it is not sensitive to one of the EP2 agonists, butaprost. Recently another subtype of PGE receptor coupled to adenylate cyclase has been identified pharmacologically and named EP4. These findings have led us to examine whether the cloned receptor is the EP4 subtype. AH23848B, a selective EP4 antagonist, not only displaced the [3H]PGE2 binding to the cloned receptor but antagonized the PGE2-stimulated cAMP formation in the receptor. In contrast, EP2 specific agonist, butaprost and 19(R)OH-PGE2 neither bound to the receptor nor stimulated the cAMP formation. These results suggest that this receptor previously reported as 'EP2' subtype is identical to the pharmacologically defined EP4 subtype and not of EP2 subtype.
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PMID:Identification of prostaglandin E receptor 'EP2' cloned from mastocytoma cells EP4 subtype. 775 93

Human promyelocytic leukaemic HL-60 cells can be differentiated with DMSO to become neutrophil-like. In this study, the prostanoid receptors linked to adenylate cyclase have been compared in human neutrophils and in differentiated HL-60 cells. Both cell types appear to express EP2 receptors as recognised by the ability of EP2 agonists and not EP1 or EP3 agonists to increase cell cyclic AMP levels, and the finding that the increase in cyclic AMP induced by PGE2 was not blocked by the EP4 receptor antagonist AH 23,848 (30 microM). Neither cell type appears to express receptors for PGI2, but human neutrophils and not differentiated HL-60 cells express receptors for PGD2. In addition, human neutrophils may contain EP3 receptors linked to a reduction in cyclic AMP levels. The lack of other prostanoid receptors coupled to adenylate cyclase in HL-60 cells suggests that these cells may provide a useful starting point for the cloning of the EP2 receptor.
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PMID:Comparison of the prostaglandin E (EP) receptor of human neutrophils and HL-60 cells differentiated with DMSO. 787 90

The cloning of the genes that encode for prostaglandin (PG) receptors has resolved much of the complexity and controversy in this area by confirming the classification proposed by Coleman, et al. Two issues that remained unresolved were (1) the inability of the EP2 agonist butaprost to interact with the cloned putative EP2 receptor and (2) molecular biological confirmation of a fourth PGE2-sensitive receptor, which was pharmacologically designated EP4. In order to provide clarification, we attempted to clone further PGE2-sensitive receptors. By using a cDNA probe that encodes for the human EP3A receptor, a cDNA clone that encoded for a novel PGE2-sensitive receptor was obtained by screening a human placenta library. This cDNA clone was transfected into COS-7 cells for pharmacological studies. The cDNA clone obtained from human placenta had only about 30% amino acid identity with cDNAs for other PG receptors, including those that encode for the previously proposed murine and human EP2 receptors. Radioligand binding studies on the novel EP receptor expressed in COS-7 cells revealed that selective EP2 agonists such as butaprost, AH 13205, AY 23626 and 19(R)-OH PGE2 all competed with 3H-PGE2 for its binding sites, whereas selective agonists for other PG receptor subtypes had minimal or no effect. This receptor was coupled to adenylate cyclase and EP2 agonists caused dose-related increases in cAMP. It appears that the cDNA described herein encodes for the pharmacologically defined EP2 receptor. Ocular studies revealed that AH 13205 decreased intraocular pressure in normal and ocular hypertensive monkeys by a mechanism that does not appear to involve inhibition of aqueous humor secretion.
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PMID:Molecular characterization and ocular hypotensive properties of the prostanoid EP2 receptor. 859 Feb 76

There are at least four subtypes of prostaglandin E (PGE) receptors. The EP1 and EP3 receptors are coupled to Ca2+ mobilization and the inhibition of adenylate cyclase, respectively, and the EP2 and EP4 receptors are coupled to the same signal transduction pathway, stimulation of adenylate cyclase. To identify the functional differences between EP2 and EP4 receptors, we examined agonist-induced desensitization of these two receptors using Chinese hamster ovary cells, which stably express these receptors. The EP4 receptor underwent short term agonist-induced desensitization, but no such desensitization was observed for the EP2 receptor. In contrast, the EP2 and EP4 receptors displayed similar patterns of down-regulation in response to prolonged exposure to PGE2. On the other hand, PGE2 is rapidly metabolized to 15-keto-PGE2 and, subsequently, to 13,14-dihydro-15-keto-PGE2. Thus, we compared the sensitivities of the two receptors to these two metabolites. The EP4 receptor markedly lost the response at the first metabolism, whereas the EP2 receptor gradually lost the response according to the degree of metabolism, having higher sensitivity to the first metabolite, 15-keto-PGE2, than the EP4 receptor. Therefore, the physiological significance of EP2 and EP4 may lie in their different sensitivities to agonist-induced short term desensitization and their differential susceptibilities to the metabolic inactivation of the agonist.
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PMID:Two Gs-coupled prostaglandin E receptor subtypes, EP2 and EP4, differ in desensitization and sensitivity to the metabolic inactivation of the agonist. 886 51

Prostaglandin (PG) E2 exerts a variety of biological activities for the maintenance of local homeostasis in the body. The effects of PGE2 are exerted by a variety of PGE receptors which are different in their signal transduction properties and are classified into four subtypes, EP1, EP2, EP3 and EP4. We have isolated the mouse cDNAs for these PGE receptors and characterized the cloned receptors. EP1, EP2, EP3 and EP4 receptors consist of 405, 362, 365 and 513 amino acid residues with a putative seven hydrophobic domains, respectively. When expressed in mammalian cells, EP1 showed elevation of intracellular [Ca2+], EP2 and EP4 stimulated adenylate cyclase and EP3 inhibited the enzyme. Northern blot and in situ hybridization analyses have shown that these subtypes are differently localized to specific tissues and cells. We have identified multiple isoforms of the EP3 receptor (EP3 alpha, EP3 beta, and EP3 gamma) which differ in their carboxy-terminal domains. These isoforms displayed identical agonist binding properties, but were functionally different in the efficiency of G protein activation, the specificity of G protein coupling, and sensitivity to agonist-induced desensitization. The diverse physiological actions of PGE2 are elicited by the molecular diversity of the receptor subtypes and isoforms distributed differently in the body.
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PMID:Molecular aspects of the structures and functions of the prostaglandin E receptors. 890 49

The effects of prostaglandin E2 (PGE2) on platelet cyclic AMP formation were examined and compared with effects on cloned prostaglandin receptors. PGE2 gave a weak stimulation of adenyl cyclase in platelets compared with the PGI2 analog Iloprost. In the presence of the adenyl cyclase stimulator forskolin, the response to PGE2 was amplified in a synergistic manner. By contrast, in the presence of Iloprost, PGE2 inhibited cyclic AMP formation. We postulate that the weak platelet response to PGE2 is due to co-localization of a PGE2 receptor that couples to stimulation of adenyl cyclase with the EP3 prostaglandin receptor that binds PGE2 tightly and inhibits adenyl cyclase. In support of this postulate, we compared the responses obtained with platelets with those of cloned EP4 (stimulatory) and EP3 (inhibitory) prostaglandin receptor subtypes and show similar dose-response curves for stimulation and inhibition of cyclic AMP formation between platelets and cloned receptors.
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PMID:Prostaglandin E2 both stimulates and inhibits adenyl cyclase on platelets: comparison of effects on cloned EP4 and EP3 prostaglandin receptor subtypes. 890 18

Prostaglandin (PG) EP4 receptor is coupled to Gs, stimulating adenylate cyclase. We tested whether cytoskeleton modulates the signal transduction of the EP4 receptor. A microtubule depolymerizing agent, colcemid, enhanced the PGE2-induced cAMP formation in the cloned EP4 receptor-expressing Chinese hamster ovary cells, but enhanced neither NaF plus AlCl3 nor forskolin-induced cAMP formation. Other microtubule depolymerizing agents, including colchicine, also induced the enhancement. These effects stemmed from the action of the agents on microtubules, because beta-lumicolchicine, an inactive isomer of colchicine, had no effect. In contrast, the microfilament depolymerizing agents did not affect the PGE2-induced cAMP formation but potentiated the enhancing effect of colcemid. This enhancement by colcemid was not due to the suppression of the desensitization of the EP4 receptor. The enhancing effect of colcemid was also observed in another Gs-coupled PGE receptor subtype, EP2 receptor. These results demonstrate that the state of microtubule assembly modulates the signal transduction of the EP4 receptor in concert with microfilament.
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PMID:Cytoskeletal regulation of the signal transduction of prostaglandin EP4 receptor. 951 73


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