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)

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

1. The present study examines the effect of naturally occurring prostanoids and prostaglandin (PG) congeners on gastrin- and pituitary adenylate cyclase-activating peptide (PACAP)-evoked histamine and pancreastatin secretion from isolated rat stomach ECL cells. 2. ECL cells (75-85% purity) were isolated from rat stomach using pronase digestion followed by repeated counter-flow elutriation and cultured for 48 h before secretion experiments. The release of histamine and pancreastatin was determined by radioimmunoassay. 3. None of the PGs tested stimulated the release of either histamine or pancreastatin. 4. PGE1 and PGE2 inhibited both gastrin- and PACAP-evoked histamine and pancreastatin secretion (IC50 = 1-2 x 10(-10) M). Most other naturally occuring prostanoids and PG congeners had no or little inhibitory effect. The PGE analogues misoprostol and sulprostone were more potent (IC50 = 0.9 x 10(-11) M and 2 x 10(-11) M respectively) than PGE1 and PGE2. The rank order of potency was misoprostol > sulprostone > PGE1 = PGE2, suggesting the involvement of the so-called EP3 receptor. 5. The effects of PGs on the stomach ECL cells may be direct or indirect, for instance through the stimulated release of somatostatin from contaminating D cells (2-3%). However, the amount of somatostatin in the cell culture after 48 h was below the limit of detection, and somatostatin immunoneutralization did not prevent misoprostol from inhibiting secretion from the ECL cells. 6. The misoprostol-induced inhibition was reversed by pertussis toxin suggesting the involvement of G-protein subunits G alpha(0) and/or G alpha(i). 7. In view of the potency by which PGE1, PGE2, misoprostol and sulprostone inhibited the stimulated release of histamine and pancreastatin, we suggest that the ECL cells represent a primary target for prostaglandins acting via an EP3 receptor in the oxyntic mucosa. 8. The results suggest that the clinically useful effect of misoprostol as an anti-ulcer drug reflects its ability to inhibit stomach ECL-cell histamine secretion.
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PMID:Prostaglandins inhibit secretion of histamine and pancreastatin from isolated rat stomach ECL cells. 972 Aug 5

In a recent communication, we demonstrated that prostaglandin E2 (PGE2) lowers basal while it ablates interleukin-1beta((IL-1beta) and transforming growth factor-beta (TGFbeta) upregulated lysyl oxidase (LO) mRNA levels. Correspondingly, PGE2 increases cyclooxygenase-1 (COX1) mRNA in diploid, human embryo lung fibroblasts (IMR90) [Roy et al., 19961. We now report that these actions by PGE2 are routed through cAMP via the PGE2, EP2 receptor. Among the PGE2 receptor types, the IMR90 predominantly express the EP2 mRNA. These cells also express EP3 and EP4 mRNA at comparatively low levels. Northern blot analyses show that 11-deoxy PGE1, an EP2/EP4 agonist, emulates the action of PGE2. In a similar manner to PGE2, 11-deoxy PGE1 decreases basal and TGF-beta induced type I collagen alpha1 (COL) mRNA, basal and IL-1beta induced LO mRNA while it increases COX1 mRNA. Sulprostone, an EP3/EP1 agonist, has no effect on the expression of these three genes. Forskolin, an adenylate cyclase activator, acts in a very similar manner to PGE2 or 11-deoxy PGE1. It suppresses both basal and TGF-beta induced COL mRNA levels. Both PGE2 and 11-deoxy PGE1 increase cAMP to a level comparable with forskolin. The role of the EP2 receptor in controlling collagen production is further underscored in the immortalized Rat-1 fibroblasts, derived from Fischer rat embryos, which do not express detectable EP2 mRNA. In these cells, PGE2 has little effect on COL mRNA level, whereas forskolin increases it. Furthermore, forskolin increases cAMP level in Rat-1 cells, whereas PGE2 does not. Overall, these results illustrate that much of the PGE2 action on the expression of COL, LO, and COX1 genes is mediated through the EP2 receptor and a subsequent increase in intracellular cAMP.
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PMID:Role of EP2 receptors and cAMP in prostaglandin E2 regulated expression of type I collagen alpha1, lysyl oxidase, and cyclooxygenase-1 genes in human embryo lung fibroblasts. 977 23

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

Prostaglandin E2 (PGE2) is an anabolic agent in vivo that stimulates bone formation by recruiting osteoblasts from bone marrow precursors. To understand which of the known PGE2 receptors (EP1-4) is involved in this process, we tested the effect of PGE2 and various EP agonists and/or antagonists on osteoblastic differentiation in cultures of bone marrow cells by counting bone nodules and measuring alkaline phosphatase activity. PGE2 increased both parameters, peaking at 100 nM, an effect that was mimicked by forskolin and was abolished by 2',3'-dideoxyadenosine (an adenylate cyclase inhibitor) and was thus cAMP dependent, pointing to the involvement of EP2 or EP4. Consistently, 17-phenyl-omega-trinor PGE2 (EP1 agonist) and sulprostone (EP3/EP1 agonist) lacked any anabolic activity. Furthermore, butaprost (EP2 agonist) was inactive, 11-deoxy-PGE1 (EP4/EP2 agonist) was as effective as PGE2, and the PGE2 effect was abolished dose dependently by the selective EP4 antagonist AH-23848B, suggesting the involvement of EP4. We also found that PGE2 increased nodule formation and AP activity when added for the initial attachment period of 24 h only. Thus this study shows that PGE2 stimulates osteoblastic differentiation in bone marrow cultures, probably by activating the EP4 receptor, and that this effect may involve recruitment of noncommitted (nonadherent) osteogenic precursors, in agreement with its suggested mode of operation in vivo.
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PMID:The anabolic effect of PGE2 in rat bone marrow cultures is mediated via the EP4 receptor subtype. 995 Jul 99

To assess the role of the conserved DPWXY motif of the seventh transmembrane domain in prostanoid receptor-mediated G protein activation, we have mutated the negatively charged Asp-318 in this motif of the Gi-coupled mouse prostaglandin EP3 receptor to uncharged but polar Asn (EP3-D318N) and to the non-polar Leu (EP3-D318L). The EP3 agonist and antagonist showed similar binding affinities for the wild-type and two mutant receptors. The wild-type and EP3-D318N receptors but not EP3-D318L receptor associated with Gi in guanine nucleotide- and pertussis toxin-sensitive manners. On the other hand, the wild-type receptor but not two mutant receptors had the ability to stimulate GTPase activity and to inhibit the adenylate cyclase. These findings demonstrate that the chemical nature of the amino acid residue at position 318 of the seventh transmembrane domain of the EP3 receptor dissociates the step of Gi association from that of subsequent Gi activation in the process of the EP3 receptor-Gi coupling.
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PMID:The key amino acid residue of prostaglandin EP3 receptor for governing G protein association and activation steps. 1008 73

To clarify the molecular basis for the prostaglandin (PG) mediated effects in adipose cells at various stages of their development, expression of mRNAs encoding receptors specific for prostaglandin E2, F2alpha and I2 (i.e. EP, FP, and IP receptors) was investigated in differentiating clonal Ob1771 pre-adipocytes, as well as in mouse primary adipose precursor cells and mature adipocytes. We have further characterized the differential expression of mRNAs encoding three subtypes of the EP receptor, i.e. EP1, EP3, and EP4, and examined the expression of mRNAs encoding the three isoforms (alpha, beta, and gamma) of the EP3 receptor. Altogether the results show that the expression of IP, FP, EP1, and EP4 receptor mRNAs was considerably more pronounced in pre-adipose cells than in adipose cells, mRNAs encoding the alpha, beta, and gamma isoforms of the EP3 receptor were all exclusively expressed in freshly isolated mature adipocytes. These data may indicate that PGI2, PGF2alpha, and PGE2 may interact directly with specific receptors in pre-adipose cells, whose transduction mechanisms are known to affect maturation related changes. In mature adipocytes, however, the equipment of mRNAs encoding the EP3 receptor isoforms is in agreement with the well known effect of PGE2 on adenylate cyclase and lipolysis in mature adipocytes.
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PMID:Differential expression of prostaglandin receptor mRNAs during adipose cell differentiation. 1048 Apr 85

To identify the E-prostanoid (EP) receptors that mediate the hemodynamic actions of PGE2, we studied acute vascular responses to infusions of PGE2 using lines of mice in which each of four EP receptors (EP1 through EP4) have been disrupted by gene targeting. In mixed groups of males and females, vasodepressor responses after infusions of PGE2 were significantly diminished in the EP2 -/- and EP4 -/- lines but not in the EP1 -/- or EP3 -/- lines. Because the actions of other hormonal systems that regulate blood pressure differ between sexes, we compared the roles of individual EP receptors in males and females. We found that the relative contribution of each EP-receptor subclass was strikingly different in males from that in females. In females, the EP2 and EP4 receptors, which signal by stimulating adenylate cyclase, mediate the major portion of the vasodepressor response to PGE2. In males, the EP2 receptor has a modest effect, but most of the vasodepressor effect is mediated by the phospholipase C-coupled EP1 receptor. Finally, in male mice, the EP3 receptor actively opposes the vasodepressor actions of PGE2. Thus the hemodynamic actions of PGE2 are mediated through complex interactions of several EP-receptor subtypes, and the role of individual EP receptors differs dramatically in males from that in females. These differences may contribute to sexual dimorphism of blood pressure regulation.
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PMID:Identification of specific EP receptors responsible for the hemodynamic effects of PGE2. 1048 12

Prostaglandin (PG) E receptors are divided into four subtypes (EP1-EP4). We investigated the EP receptor subtype involved in PGE2-stimulated mucus secretion by rabbit gastric epithelial cells. Northern blot analysis revealed that epithelial cells express EP3 and EP4 receptor mRNAs, but neither EP1 nor EP2 receptor mRNAs were detected. PGE2, 11-deoxy-PGE1 (an EP3/EP4/EP2 agonist) and 16,16-dimethyl-PGE2 (an EP3/EP2/EP4 agonist) concentration-dependently promoted mucus secretion. In contrast, 17-phenyl-PGE2 (an EP3/EP1 agonist), sulprostone (an EP3/EP1 agonist), and butaprost (an EP2 agonist) failed to stimulate secretion. The effective concentrations of PGE2, 11-deoxy-PGE1, and 16,16-dimethyl-PGE2 were associated with their affinities for the EP4 receptor. In addition, PGE2, 11-deoxy-PGE1, and 16,16-dimethyl-PGE2 increased cyclic AMP (cAMP) production, but the other prostanoids had no effect. SQ22536 [9-(tetrahydro-2'-furyl)adenine; an adenylate cyclase inhibitor] inhibited both the increased cAMP production and mucus secretion induced by PGE2, 11-deoxy-PGE1, and 16,16-dimethyl-PGE2. H-89 (N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinoline sulfonamide; a protein kinase A inhibitor) also abolished the stimulatory effects of the prostanoids on mucus secretion, but calphostin C (a protein kinase C inhibitor) did not. These results indicate that PGE2 promotes mucus secretion by rabbit gastric epithelial cells, mediated through EP4 receptor stimulation and the subsequent activation of protein kinase A.
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PMID:EP4 receptor mediation of prostaglandin E2-stimulated mucus secretion by rabbit gastric epithelial cells. 1059 Nov 56


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