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)

Dietary essential fatty acids are the precursors for eicosanoids. Among the eicosanoids derived from arachidonic acid, prostaglandin (PG) E2 is known to possess immunosuppressive actions. Thus, it has been a prevailing hypothesis that the immuno-modulatory roles of dietary fatty acids are mediated at least in part through the alteration of PG biosynthesis. PGs exert their biological effects through their cognate receptors. There are four subtypes of PGE receptors (EP1, EP2, EP3, and EP4) so far identified. Although the association of EP receptors with G proteins coupled to adenylate cyclase and the mobilization of intracellular calcium are well documented, downstream signaling pathways for these receptors are virtually unknown. Identification of downstream signaling pathways for each subtype of EP receptors and target genes regulated by the activation of the receptor will help with our understanding of the mechanism by which dietary fatty acids affect immune responses through the modulation of PGE2 biosynthesis. Emerging evidence suggests that fatty acids can additionally act as second messengers, regulators of signal transducing molecules or transcription factors. Acylation with long-chain fatty acids can occur on a variety of signaling molecules and can affect their membrane translocation and functions. Dietary fatty acids can alter functional properties of lipid mediators by changing the composition of acyl moieties of these molecules. Evidence accumulated recently indicates that long-chain unsaturated fatty acids and their metabolites bind and activate peroxisome proliferator-activated receptors (PPARs). PPARs are nuclear hormone receptors and transcription factors that regulate the expression of broad arrays of genes involved not only in lipid and glucose metabolism, but also in immune and inflammatory responses. PPARs may therefore be important cellular targets that mediate modulation of immune responses by dietary fatty acids. Together, it becomes clear now that multiple steps in various receptor-mediated signaling pathways can be modulated by dietary fatty acids. It will be a challenging task to quantitatively determine how different fatty acids alter functional properties of multitude of signaling components and final cellular responses. Elucidating the mechanism of actions of fatty acids on receptor-mediated signaling pathways in immuno-competent cells will provide a new insight for understanding the immuno-modulatory roles of dietary fatty acids.
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PMID:Fatty acids and immune responses--a new perspective in searching for clues to mechanism. 1094 Mar 41

In the present study, we examined whether prostaglandin (PG) E2 and PGI2 regulated intercellular adhesion molecule-1 (ICAM-1) expression in human oral gingival epithelial cells stimulated with tumor necrosis factor alpha (TNF alpha). TNF alpha potently induced ICAM-1 expression in a dose- and time-dependent fashion. PGE2 and carbacyclin (a stable analogue of PGI2) significantly decreased ICAM-1 expression in TNF alpha-challenged oral gingival epithelial cells. Next, of the four subtypes of PGE2 receptors (EP1, EP2, EP3 and EP4), we examined which subtype(s) mediated inhibition of TNF alpha-induced ICAM-1 expression by PGE2. 11-deoxy-PGE2, an EP2/EP4 agonist, significantly suppressed TNF alpha-induced ICAM-1 expression, whereas butaprost, an EP2 agonist, sulprostone, an EP1/EP3 agonist, and ONO-AP-324, an EP3 agonist, caused no effect on it. By reverse transcriptase-polymerase chain reaction, expression of EP4 mRNA was detected in oral gingival epithelial cells. Dibutyryl cAMP, a cAMP analogue, and forskolin, a direct activator of adenylate cyclase, significantly inhibited TNF alpha-induced ICAM-1 expression in oral gingival epithelial cells. From these results, we suggest that PGE2 and PGI2 inhibit TNF alpha-elicited ICAM-1 expression by cAMP-dependent pathways via EP4 receptors and IP receptors, respectively.
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PMID:Prostaglandins E2 and I2 downregulate tumor necrosis factor alpha-induced intercellular adhesion molecule-1 expression in human oral gingival epithelial cells. 1115 20

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

In the present study, the effect of prostaglandin E2 (PGE2) on intercellular adhesion molecule-1 (ICAM-1) expression in human gingival fibroblasts (HGF) stimulated with lipopolysaccharides (LPS) was investigated. LPS were isolated from periodontopathic bacteria, Actinobacillus actinomycetemcomitans (A. actinomycetemcomitans) and Porphyromonas gingivalis (P. gingivalis), by the phenol-water method and Escherichia coli (E. coli) LPS was used as a control. PGE2 significantly inhibited A. actinomycetemcomitans-, P. gingivalis- and E. coli-LPS-induced ICAM-1 expression. Next, of four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4), we examined which subtype(s) was involved in inhibition of LPS-elicited ICAM-1 expression by PGE2. Eleven-deoxy-PGE1, a selective EP2/EP4 agonist, and butaprost, a selective EP2 agonist, attenuated A. actinomycetemcomitans-, P. gingivalis- and E. coli-LPS-elicited ICAM-1 expression, although butaprost was less potent than PGE2 and 11-deoxy-PGE1. Sulprostone, an EP1/EP3 agonist, and ONO-AP-324, an EP3 agonist, was inert to the LPS-elicited ICAM-1 expression. Furthermore, dibutyryl cAMP, a cAMP analogue, and forskolin, an adenylate cyclase activator, downregulated A. actinomycetemcomitans-, P. gingivalis- and E. coli-LPS-elicited ICAM-1 expression in HGF. Our data suggest that PGE2 downregulates A. actinomycetemcomitans- and P. gingivalis-LPS-induced ICAM-1 expression in HGF, via EP2/EP4 receptors by cAMP-dependent signaling pathways. The cAMP-elevating agents such as EP2/EP4 receptor activators may serve to control inflammatory and immune responses in periodontal disease.
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PMID:Downregulation of lipopolysaccharide-induced intercellular adhesion molecule-1 expression via EP2/EP4 receptors by prostaglandin E2 in human fibroblasts. 1132 62

Prostaglandin E2 (PGE2) is an important mediator of diverse biologic functions in many tissues and binds with high affinity to four cell surface, seven-transmembrane domain, G protein-coupled receptors (EP1-EP4). The EP4 receptor subtype has a long intracellular carboxy-terminal region and is functionally coupled to adenylate cyclase, resulting in elevated intracellular cyclic adenosine 5' monophosphate (cAMP) levels upon activation. To further study EP4 receptor subtype function, a canine kidney cDNA library was screened and three clones were isolated and sequenced. The longest clone was 3,103 bp and contained a single open reading frame of 1,476 bp, potentially encoding a protein of 492 amino acids with a predicted molecular weight of 53.4 kDa. Sequence analysis of this open reading frame reveals 89% identity to the human EP4 protein coding region at the nucleotide level and 90% identity when the putative canine and human protein sequences are compared. Northern blot analysis showed relatively high levels of canine EP4 expression in heart, lung and kidney, while Southern blot analysis of canine genomic DNA suggests the presence of a single copy gene. Following transfection of canine EP4 into CHO-KI cells, Scatchard analysis revealed a dissociation constant of 24 nM for PGE, while competition binding studies using 3H-PGE2 as ligand demonstrated specific displacement by PGE2 prostaglandin E, (PGE1), and prostaglandin A3 (PGA3). Treatment with PGE2 also resulted in increased levels of cAMP in transfected, but not in parental, CHO-KI cells. In contrast, butaprost, an EP2 selective ligand, and sulprostone, an EP1/EP3 selective ligand, did not bind to this receptor at the maximal concentration used (320 nM). To further investigate secondary signaling, the canine EP4 cDNA was truncated to produce an 1,117 bp fragment encoding a 356 amino acid protein lacking the intracellular carboxy-terminus. When transfected, this truncated cDNA produced a protein with a dissociation constant of 11 nM for PGE2 and a binding and cAMP accumulation profile similar to that of the full-length protein. Both full-length and truncated canine EP4 underwent short term PGE2-induced desensitization as shown by a lack of continuing cAMP accumulation after the initial PGE2 stimulation, suggesting no involvement of the C-terminal intracellular tail. This result is in contrast to that reported for the human EP4 receptor, where residues within the C-terminal intracellular tail were shown to mediate short term, ligand induced desensitization.
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PMID:Molecular cloning and functional characterization of the canine prostaglandin E2 receptor EP4 subtype. 1144 89

We investigated the mechanism underlying vascular endothelial growth factor (VEGF) synthesis stimulated by prostaglandin E1 (PGE1) in osteoblast-like MC3T3-E1 cells. PGE1 induced the phosphorylation of both p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase. SB203580, a specific inhibitor of p38 MAP kinase, inhibited the PGE1-stimulated VEGF synthesis as well as PGE1-induced phosphorylation of p38 MAP kinase. PD98059, an inhibitor of the upstream kinase that activates p44/p42 MAP kinase, which reduced the PGE1-induced phosphorylation of p44/p42 MAP kinase, had little effect on the VEGF synthesis stimulated by PGE1. AH-6809, an antagonist of the subtypes of the PGE receptor, EP1 and EP2, or SC-19220, an antagonist of EP1 receptor, did not inhibit the PGE1-induced VEGF synthesis. H-89, an inhibitor of cAMP-dependent protein kinase, and SQ22536, an inhibitor of adenylate cyclase, reduced the VEGF synthesis induced by PGE1. Cholera toxin, an activator of G(s), and forskolin, an activator of adenylate cyclase, induced VEGF synthesis. SB203580 and PD169316, another specific inhibitor of p38 MAP kinase, reduced the cholera toxin-, forskolin- or 8bromo-cAMP-stimulated VEGF synthesis. However, PD98059 failed to affect the VEGF synthesis stimulated by cholera toxin, forskolin or 8-bromoadenosine-3',5'-cyclic monophosphate (8bromo-cAMP). SB203580 reduced the phosphorylation of p38 MAP kinase induced by forskolin or 8bromo-cAMP. These results strongly suggest that p44/p42 MAP kinase activation is not involved in the PGE1-stimulated VEGF synthesis in osteoblasts but that p38 MAP kinase activation is involved.
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PMID:p38 mitogen-activated protein (MAP) kinase but not p44/p42 MAP kinase is involved in prostaglandin E1-induced vascular endothelial growth factor synthesis in osteoblasts. 1152 43

Prostaglandin E2 (PGE2) has been reported to control angiogenesis and play an important role in wound healing in soft tissues, although the precise mechanism is still unknown. Since basic fibroblast growth factor (bFGF) has been reported to generate neovascularization, PGE2 and bFGF might work closely, or one might control the expression of the other. In this study, we demonstrate that PGE2 enhances the expression of bFGF in normal human fibroblasts, and that calcium ionophore, A23187, and adenylate cyclase activator, forskolin, also enhances the expression bFGF mRNA. These results suggest that enhancement of bFGF mRNA stimulated by PGE2 is mainly controlled through EP1 or EP2 and EP4 receptor. In conclusion, our findings suggest that the mechanism of PGE2-induced angiogenesis and wound hearing in soft tissue could be mediated by bFGF through EP1 or EP2 and EP4 receptor.
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PMID:Prostaglandin E2 regulates the expression of basic fibroblast growth factor messenger RNA in normal human fibroblasts. 1156 93

Costimulatory molecules play important roles in immune responses. In the present study we investigated the effects of PGE(2) on the expression of ICAM-1, B7.1, and B7.2 on monocytes in IL-18-stimulated PBMC using FACS analysis. Addition of PGE(2) to PBMC inhibited ICAM-1 and B7.2 expression elicited by IL-18 in a concentration-dependent manner. We examined the involvement of four subtypes of PGE(2) receptors, EP1, EP2, EP3, and EP4, in the modulatory effect of PGE(2) on ICAM-1 and B7.2 expression elicited by IL-18, using subtype-specific agonists. ONO-AE1-259-01 (EP2R agonist) inhibited IL-18-elicited ICAM-1 and B7.2 expression in a concentration-dependent manner with a potency slightly less than that of PGE(2), while ONO-AE1-329 (EP4R agonist) was much less potent than PGE(2). The EP2/EP4R agonist 11-deoxy-PGE(1) mimicked the effect of PGE(2) with the same potency. ONO-D1-004 (EP1R agonist) and ONO-AE-248 (EP3R agonist) showed no effect on IL-18-elicited ICAM-1 or B7.2 expression. These results indicated that EP2 and EP4Rs were involved in the action of PGE(2). Dibutyryl cAMP and forskolin down-regulated ICAM-1 and B7.2 expression in IL-18-stimulated monocytes. As EP2 and EP4Rs are coupled to adenylate cyclase, we suggest that PGE(2) down-regulates IL-18-induced ICAM-1 and B7.2 expression in monocytes via EP2 and EP4Rs by cAMP-dependent signaling pathways. The fact that anti-B7.2 as well as anti-ICAM-1 Ab inhibited IL-18-induced cytokine production implies that PGE(2) may modulate the immune response through regulation of the expression of particular adhesion molecules on monocytes via EP2 and EP4Rs.
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PMID:Prostaglandin E(2) inhibits IL-18-induced ICAM-1 and B7.2 expression through EP2/EP4 receptors in human peripheral blood mononuclear cells. 1197 Sep 88

In the present study, we examined the effect of prostaglandin (PG) E2 on interleukin (IL) -12 production in monocytes stimulated with a combination of lipopolysaccharide (LPS) from Actinobacillus actinomycetemcomitans and interferon-gamma (A. actinomycetemcomitans-LPS/IFN-gamma). Indomethacin, a cyclooxygenase inhibitor, enhanced IL-12 production, but inhibited PGE2 generation in A. actinomycetemcomitans-LPS/IFN-gamma-stimulated monocytes. Exogenous PGE2 inhibited IL-12 release in the cells. EP2, EP3 and EP4 receptor mRNA expression was detected in monocytes by reverse transcription-polymerase chain reaction. 11-deoxy-PGE1 (an EP2/EP4 agonist) inhibited IL-12 production in A. actinomycetemcomitans-LPS/IFN-gamma-challenged monocytes, whereas butaprost (an EP2 agonist) or ONO-AP-324 (an EP3 agonist) had no effect on IL-12 production. Dibutyryl cAMP, a cAMP analogue, and forskolin, an adenylate cyclase activator, mimicked depression of IL-12 production by PGE2. From these results, we suggest that PGE2 inhibits IL-12 production via EP4 receptors by cAMP-dependent pathways in A. actinomycetemcomitans-LPS/IFN-gamma-challenged monocytes.
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PMID:Prostaglandin E2 downregulates interleukin-12 production through EP4 receptors in human monocytes stimulated with lipopolysaccharide from Actinobacillus actinomycetemcomitans and interferon-gamma. 1275 65

The prostaglandin E2 (PGE(2)) EP2 receptor (EP2R) type is G protein coupled (GPCR) and links to Galphas. Through this receptor PGE(2) activates cAMP production. The bradykinin (BK) B2 receptor (BKB2R) is also a GPCR but links to Galphaq and Galphai and does not activate cAMP production in response to bradykinin. In an attempt to convert the BKB2R into a Galphas-linked adenylate cyclase-activating receptor we proceeded to make global and discrete motif replacements of the intracellular (IC) face of the BKB2R with the corresponding regions of the human EP2R. With this approach we produced hybrid receptors which, when stably transfected into wild type (WT) Rat-1 cells, bound BK but produced cAMP. Replacement of the second loop (IC2), third loop (IC3), the entire C terminus, and the distal C terminus resulted in receptors which bound BK. However, only the IC2 and IC3 exchanges resulted in cAMP-producing receptors. Of these two regions, the IC2 exchange was by far the better cAMP-generating receptor, producing cAMP at approximately 6.6-fold above WT BKB2R or approximately one fourth the amount produced by WT EP2R-transfected Rat-1 cells. Both human and rat EP2R and human beta2-adrenergic receptor exchanges of the IC2 produced equal quantities of cAMP. Focusing on the rBKB2R/hEP2R IC2 chimeras, the region consisting of residues 136-147 (BKB2R residue numbering) proved to contain a cAMP-generating motif. Within this region, the proximal six amino acids from the EP2R (HPYFYQ) at position 136-141 proved crucial for cAMP production (10-fold over WT BKB2R). The distal part of this region, the six residues at 142-147, played no role in cAMP production. On the other hand, the ALV motif of the BKB2R IC2, residues 133-135, proved important with respect to phosphatydilinositol (PI) turnover. Replacing the entire IC2 of BKB2R resulted in poor PI turnover, while including the AVL of BKB2R retained approximately half of the WT PI turnover. With respect to receptor uptake, all the IC2 mutants endocytosed as WT BKB2R (60% in 1h). However, the exchange of the distal and the whole C termini resulted in a marked drop in endocytosis (30% in 1h). These results demonstrate that the construction of a cAMP-producing BKB2/EP2 receptor hybrid is possible, with the IC2 region distal to DRYLALV proving important to Galphas linkage and the LALV motif within the IC2 of BKB2R and the region proximal to it proving important for Galphaq and Galphai linkage. Additionally, our results confirm the importance of the distal C terminus in determining receptor uptake.
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PMID:Chimeric exchanges within the bradykinin B2 receptor intracellular face with the prostaglandin EP2 receptor as the donor: importance of the second intracellular loop for cAMP synthesis. 1280 12


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