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)

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

The structure-activity relations and signal transduction pathways for the anabolic effects of prostaglandins were examined in cultured fetal rat calvariae. In the presence of cortisol prostaglandins of the E and F series (10(-9) to 10(-5) M) produced a dose-related increase in [3H]thymidine incorporation up to 4-fold at 24 h. Prostaglandin E2 (PGE2) was also effective in the absence of cortisol. Butaprost (10(-6) M), a selective EP-2 receptor agonist, produced partial stimulation. Prostaglandin D2, prostacyclin, sulprostone, an EP-1 and EP-3 receptor agonist, and fluprostenol, an FP receptor agonist, were ineffective. Forskolin (10(-4) M) increased [3H]thymidine incorporation 3-fold, while phorbol myristate acetate (PMA) (10(-6) M) produced a 1.8-fold increase. Isobutylmethylxanthine (IBMX) increased [3H]thymidine incorporation in control cultures, in the absence of cortisol, and increased the response to PGE2 in control and cortisol-treated cultures. [3H]proline incorporation into collagen and noncollagen protein was measured in the continuous presence of prostaglandins and cortisol for 72-96 h (continuous model) or when prostaglandins and cortisol were applied for 24 h, followed by culture for 48 h in control medium (on/off model). The effects on collagen were greater than on noncollagen proteins, so that the percent of collagen synthesis increased. The effects of prostaglandins and forskolin paralleled their mitogenic effects. PMA increased only noncollagen protein. Indomethacin did not diminish the anabolic response, while aphidicolin produced only partial inhibition. We conclude that the anabolic effects of prostaglandins on replication and differentiation of osteoblasts are likely to be mediated by an EP-2 receptor that stimulates adenylate cyclase.
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PMID:Anabolic effects of prostaglandins in cultured fetal rat calvariae: structure-activity relations and signal transduction pathway. 886 99

Human promyeloid HL-60 cells are differentiated by all-trans retinoic acid (RA) to granulocytes, and prostaglandin (PG) E2 potentiates the RA-induced differentiation. Here we examined which subtype of PGE receptors was involved in this potentiating activity of PGE2. Northern blot analysis demonstrated that HL-60 cells expressed three subtypes of PGE receptor, EP2, EP3, and EP4. Among various EP agonists, and EP2-selective agonist, butaprost, preferentially potentiated the RA-induced differentiation of HL-60 cells. Butaprost not only decreased the half-maximal concentration of RA but also increased the maximal level of the differentiation. Butaprost concentration-dependently stimulated the cAMP formation, and 8-Br-cAMP strongly potentiated the RA-induced differentiation. These results demonstrate that the EP2 receptor enhances the RA-induced differentiation of HL-60 cells via stimulation of adenylate cyclase.
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PMID:Potentiation of retinoic acid-induced differentiation of HL-60 cells by prostaglandin EP2 receptor. 978 84

Using monolayers of bovine aortic endothelial cells (BAEC) in modified Boyden chambers, we examined the role of prostaglandins (PGs) in the bradykinin (BK)-induced increase of albumin permeability. BK induced a concentration-dependent increase of the permeability of BAEC, which reached 49.9 +/- 1% at the concentration of 10(-8) M. Two inhibitors of the prostaglandin G/H synthase, indomethacin (2.88 microM) and ibuprofen (10 microM), potentiated BK-induced permeability 1.8- and 3.9-fold, respectively. Exogenously administered PGE2 and iloprost, a stable analog of prostacyclin, attenuated the effect of BK in a concentration-dependent manner. Butaprost equally reduced the effect of BK, suggesting the participation of the EP2 receptor in this phenomenon. However, the EP4-selective antagonist AH-23848 did not significantly inhibit the protective effect of PGE2. The inhibitory effect of PGE2 was reversed by the adenylate cyclase inhibitor MDL-12330A (10 microM). These results suggest that BK-induced increase of permeability of BAEC monolayer to (125)I-labeled albumin is negatively regulated by PGs. This postulated autocrine activity of PGs may involve an increase in the intracellular level of cAMP.
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PMID:Permeability of endothelial monolayers to albumin is increased by bradykinin and inhibited by prostaglandins. 1123 14

The expression and regulation of the PGE receptors, EP(2) and EP(4), both of which are coupled to the stimulation of adenylate cyclase, were examined in peritoneal resident macrophages from C3H/HeN mice. mRNA expression of EP(4) but not EP(2) was found in nonstimulated cells, but the latter was induced by medium change alone, and this induction was augmented by LPS. mRNA expression of EP(4) was down-regulated by LPS but not by medium change. PGE(2) increased the cAMP content of both LPS-treated and nontreated cells. ONO-604, an EP(4) agonist, also increased cAMP content in nonstimulated cells and in cells treated with LPS for 3 h, but not for 6 h. Butaprost, an EP(2) agonist, was effective only in the cells treated with LPS for 6 h. The inhibitory effects of ONO-604 on TNF-alpha and IL-12 production were equipotent with PGE(2) at any time point, but the inhibitory effects of butaprost were only seen from 14 h after stimulation. PGE(2) or dibutyryl cAMP alone, but not butaprost, reduced EP(4) expression, and indomethacin reversed the LPS-induced down-regulation of EP(4), indicating that the down-regulation of EP(4) is mediated by LPS-induced PG synthesis and EP(4) activation. Indeed, when we used C3H/HeJ (LPS-hyporesponsive) macrophages, such reduction in EP(4) expression was found in the cells treated with PGE(2) alone, but not in LPS-treated cells. In contrast, up-regulation of EP(2) expression was again observed in LPS-treated C3H/HeJ macrophages. These results suggest that EP(4) is involved mainly in the inhibition of cytokine release, and that the gene expression of EP(2) and EP(4) is differentially regulated during macrophage activation.
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PMID:The expression of prostaglandin E receptors EP2 and EP4 and their different regulation by lipopolysaccharide in C3H/HeN peritoneal macrophages. 1125 29

Cytochrome P-450 is an important bioactivation-detoxification system in vivo. Its expression is regulated by foreign chemicals and dietary factors, and lipids have been found to regulate its gene expression. We showed previously that prostaglandin E(2) (PGE(2)), a fatty acid metabolite, down-regulates cytochrome P-450 2B1 (CYP 2B1) expression induced by phenobarbital. The objective of the present study was to determine whether PGE(2) type 2 receptor (EP(2))-which is coupled to Gs-protein when bound by PGE(2), leading to cAMP production-is involved in this down-regulation. We also determined the possible roles of EP(2) downstream pathways in this down-regulation. We used a primary rat hepatocyte culture model in which EP(2) was shown to be present to study this question. The intracellular cAMP concentration in primary rat hepatocytes was significantly higher after treatment with 1microM PGE(2) than after treatment with 0, 0.01, or 0.1microM PGE(2). Butaprost, an EP(2) agonist, down-regulated CYP 2B1 expression in a dose-dependent manner. SQ22536, an adenylate cyclase inhibitor, reversed the down-regulation by PGE(2) as did H-89, a protein kinase A inhibitor. These results suggest that EP(2) and the downstream pathways of cAMP and protein kinase A are involved in the down-regulation of CYP 2B1 expression by PGE(2) in the presence of phenobarbital.
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PMID:Prostaglandin E2 down-regulation of cytochrome P-450 2B1 expression induced by phenobarbital is through EP2 receptor in rat hepatocytes. 1562 32

The activation of glutamate receptors, particularly N-methyl-D-aspartate (NMDA) receptors, initiates ischemic cascade in the early stages of cerebral ischemia. Postischemia, cerebral ischemia is also associated with an inflammatory reaction that contributes to tissue damage. The up-regulation of neuronal cyclooxygenase-2 (COX-2) and elevation of prostaglandin E2 (PGE2) have been reported to occur after cerebral ischemic insult. We therefore studied whether the COX-2 reaction product PGE2 affects glutamate receptor-mediated cell death in cultured rat cortical cells. PGE2 was found to augment NMDA-mediated cell death. The transcription of EP1, EP2, EP3 and EP4 PGE2 receptor genes was investigated using reverse transcriptase-polymerase chain reaction (RT-PCR). EP1, EP2 and EP3 receptor genes were found in cortical cells. Butaprost (an EP2 agonist) markedly enhanced NMDA-mediated cell death, whereas 17-phenyl trinor-PGE2 (an EP1 agonist) and sulprostone (an EP3 agonist) had little effect. Both PGE2 and butaprost elevated cAMP intracellular levels in the cortical cells; moreover, forskolin, an activator of adenylate cyclase, enhanced NMDA-mediated cell death. These results suggest that PGE2, acting via EP2 receptors, aggravates excitotoxic neurodegeneration by a cAMP-dependent mechanism.
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PMID:Prostaglandin E2 deteriorates N-methyl-D-aspartate receptor-mediated cytotoxicity possibly by activating EP2 receptors in cultured cortical neurons. 1630 9

The interstitial cells of Cajal (ICC) are pacemaker cells in gastrointestinal tract and generate an electrical rhythm in gastrointestinal muscles. We investigated the possibility that PGE(2) might affect the electrical properties of cultured ICC by activating ATP-dependent K(+) channels and, the EP receptor subtypes and the subunits of ATP-dependent K(+) channels involved in these activities were identified. In addition, the regulation of intracellular Ca(2+) ([Ca(2+)](i)) mobilization may be involved the action of PGE(2) on ICC. Treatments of ICC with PGE(2) inhibited electrical pacemaker activities in the same manner as pinacidil, an ATP-dependent K(+) channel opener and PGE(2) had only a dose-dependent effect. Using RT-PCR technique, we found that ATP-dependent K(+) channels exist in ICC and that these are composed of K(ir) 6.2 and SUR 2B subunits. To characterize the specific membrane EP receptor subtypes in ICC, EP receptor agonists and RT-PCR were used: Butaprost (an EP(2) receptor agonist) showed the actions on pacemaker currents in the same manner as PGE(2). However sulprostone (a mixed EP(1) and EP(3) agonist) had no effects. In addition, RT-PCR results indicated the presence of the EP(2) receptor in ICC. To investigate cAMP involvement in the effects of PGE(2) on ICCs, SQ-22536 (an inhibitor of adenylate cyclase) and cAMP assays were used. SQ-22536 did not affect the effect of PGE(2) on pacemaker currents, and PGE(2) did not stimulate cAMP production. Also, we found PGE(2) inhibited the spontaneous [Ca(2+)](i) oscillations in cultured ICC. These observations indicate that PGE(2) alters pacemaker currents by activating the ATP-dependent K(+) channels comprised of K(ir) 6.2-SUR 2B in ICC and this action of PGE(2) are through EP(2) receptor subtype and also the activation of ATP-dependent K(+) channels involves intracellular Ca(2+) mobilization.
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PMID:Activating of ATP-dependent K+ channels comprised of K(ir) 6.2 and SUR 2B by PGE2 through EP2 receptor in cultured interstitial cells of Cajal from murine small intestine. 1716 24

Dopaminergic neurons in the substantia nigra (SN) selectively die in Parkinson's disease (PD), but it is unclear how and why this occurs. Recent findings implicate prostaglandin E(2) (PGE(2)) and two of its four receptors, namely EP1 and EP2, as mediators of degenerative and protective events in situations of acute and chronic neuronal death. EP1 activation can exacerbate excitotoxic damage in stroke models and our recent study showed that EP1 activation may explain the selective sensitivity of dopaminergic neurons to oxidative stress. Conversely, EP2 activation may be neuroprotective, although toxic effects have also been demonstrated. Here we investigated if and how EP2 activation might alter the survival of dopaminergic neurons following selective low-level oxidative injury evoked by the neurotoxin 6-hydroxydopamine (6-OHDA) in primary neuronal cultures prepared from embryonic rat midbrain. We found that cultured dopaminergic neurons displayed EP2 receptors. Butaprost, a selective EP2 agonist, significantly reduced 6-OHDA neurotoxicity. EP2 receptors are coupled to stimulatory G-proteins (Gs), which activate adenylate cyclase, increasing cAMP synthesis, which then activates protein kinase A (PKA). Both dibutyryl cAMP and forskolin reduced dopaminergic cell loss after 6-OHDA exposure. Conversely, KT5720 and H-89, two structurally distinct high-affinity PKA inhibitors, abolished the protective effect of butaprost, implicating cAMP-dependent PKA activity in the neuroprotection by EP2 activation. Finally, we show that melanized dopaminergic neurons in the human SN express EP2. This pathway warrants consideration as a neuroprotective strategy for PD.
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PMID:Prostaglandin receptor EP2 protects dopaminergic neurons against 6-OHDA-mediated low oxidative stress. 1859 41

The interstitial cells of Cajal (ICCs) are pacemakers in the gastrointestinal tract. The possibility of whether imatinib mesylate, a Kit receptor tyrosine kinase inhibitor, modulates pacemaker activities in the ICC was examined using the whole cell patch clamp technique. Imatinib decreased the amplitude of pacemaker potentials in a dose-dependent manner in current-clamp mode. Because the effects of imatinib on pacemaker potentials were the same as those of pinacidil, we examined the effect of glibenclamide on ICC exposed to imatinib. The effects of imatinib on pacemaker potentials were blocked by glibenclamide. To see whether the production of prostaglandins (PGs) is involved in the inhibitory effect of imatinib on pacemaker potentials, we tested the effects of naproxen (a non-selective cyclooxygenase inhibitor) and AH6809 (a prostaglandin EP1 and EP2 receptor antagonist). Naproxen and AH6809 blocked the inhibitory effects of imatinib on ICC. Butaprost (an EP2 receptor agonist) showed the actions on pacemaker potentials in the same manner as imatinib. However, SC 19220 (an EP1 receptor antagonist) has no effects. To investigate the involvement of cAMP and protein kinase A (PKA) in the effects of imatinib on ICC, SQ 22536 (an inhibitor of adenylate cyclase) and mPKAI (an inhibitor of myristoylated PKA) were used. Both SQ-22536 and mPKAI blocked the imatinib-mediated inhibition of pacemaker potentials. However, the protein kinase C (PKC) inhibitors did not block the imatinib-mediated inhibition of pacemaker potentials. These results indicate that imatinib inhibits the pacemaker potentials of ICC by activating ATP-sensitive K(+) channels and PKA-dependent, PKC-independent manner.
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PMID:Effects of imatinib mesylate in interstitial cells of Cajal from murine small intestine. 2052 65


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