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)

Activated macrophages produce a number of proinflammatory cytokines including IL-6, JE, MIP-1 alpha and MIP-1 beta. The induction requirements for production of either IL-6 or the MIP-1 related inflammatory proteins (MIP-1 alpha, MIP-1 beta, and JE) have been analyzed independently using fibroblasts, monocytes, or endothelial cells. However, little is known about the regulation of these cytokines in macrophages. Since activated macrophages produce prostaglandins (PGE2) which may participate in the autoregulation of cytokine production by stimulation of adenylate cyclase and the induction of cAMP-dependent signal pathways, we determined the effects of PGE on the production of IL-6 and MIP-1-related proteins. Murine macrophage cell lines were incubated with PGE1, PGE2, cholera toxin, or dibutyryl cAMP in the presence of absence suboptimal doses of LPS. Pharmacologic agents alone did not induce IL-6 production but incubation of macrophages with combinations of adenylate cyclase stimulators and LPS or dcAMP and LPS led to the dose-dependent enhancement of IL-6 secretion and mRNA expression. In contrast, PGE1 inhibits LPS-induced JE, MIP-1 alpha, and MIP-1 beta mRNA expression and this inhibition is partially dependent on a cAMP-mediated pathway of signal transduction. In previous work we demonstrated that IFN-gamma and PMA do not stimulate the production of IL-6 by macrophages. Here we show that incubation of macrophages with either IFN-gamma or PMA induces the expression of JE, MIP-1 alpha and MIP-1 beta mRNA expression. JE mRNA expression is much more responsive to the stimulatory effects of IFN-gamma than are the MIP-1 genes. Finally, PGE inhibits PMA and IFN-gamma-induced JE and MIP-1-related mRNA expression.
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PMID:Differential regulation of interleukin-6, macrophage inflammatory protein-1, and JE/MCP-1 cytokine expression in macrophage cell lines. 185 Mar 27

Prostacyclin is a critical mediator of structure and function in the pulmonary circulation, causing both the inhibition of vascular smooth muscle growth and vasodilation via the stimulation of adenylate cyclase. To examine the potential role of alterations in prostacyclin production or mechanism of action in chronic hypoxic pulmonary hypertension, we determined the effects of prolonged (7 d) in vivo hypoxia on in vitro prostacyclin synthesis and mediation of adenylate cyclase activity in rat main pulmonary arteries. In control arteries prostacyclin production exceeded that of prostaglandin (PG) E2 by 25-fold, with 42% originating from the endothelium. Studies utilizing indomethacin revealed that endogenous prostaglandins mediate at least 69% of basal adenylate cyclase activity. Prostacyclin-stimulated enzyme activity was enhanced by exogenous GTP, indicating that this is a receptor-mediated process involving G protein amplification. Comparable dose-related responses to prostacyclin and PGE2 suggest that these agents may activate a common receptor. After 7 d of in vivo hypoxia there was a 2.7-fold increase in in vitro prostacyclin production, with equivalent increases in synthesis in the endothelium and vascular smooth muscle. However, despite this increase there was no change in basal adenylate cyclase activity, and this was associated with attenuated sensitivity of the enzyme to prostacyclin stimulation. Concomitant diminution of the response to beta-adrenergic stimulation, with previously-demonstrated beta receptor downregulation and unaltered postreceptor-mediated activity, suggests that the blunted response to prostacyclin is due to receptor downregulation. Parallel studies of the thoracic aorta indicated that these changes are specific to the pulmonary artery. It is postulated that attenuation of the response of adenylate cyclase to prostacyclin may contribute to the structural changes and hypertension observed in the pulmonary vasculature of the rat with chronic hypoxia.
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PMID:Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat. 186 58

Osteoblastic cells were cloned by culturing rat calvariae cells in agarose in the presence of TGF-beta and EGF. Two bone cell lines were established by immortalizing such an osteoblastic clonal cell population by the introduction of the avian v-mycOK10 gene in the form of a mouse ecotropic retrovirus. Although originating from the same clonal cell population, the two lines exhibited somewhat differing properties. IRC10/30-myc1 expressed alkaline phosphatase (AP), showed PTH- and PGE2-induced cAMP production, synthesized mainly collagen type I and a minor fraction of type III, and produced mRNA for the bone-specific protein osteocalcin. IRC10/30-myc3 did not express AP, showed no PTH responsiveness, and synthesized only about one-third as much collagen as IRC10/30-myc1 (4 versus 12% of total protein synthesis). However, the cell line IRC10/30-myc3 was induced to synthesize cAMP by PGE2 and produced osteocalcin mRNA. When cultured in vivo in diffusion chambers, both lines proved to be osteogenic. Besides bone, both lines also formed cartilage and fibrous tissue. Thus, by immortalizing a clonal cell population of the osteoblastic phenotype, cell lines expressing varying properties can emerge. Furthermore, the expression of alkaline phosphatase and PTH-inducible adenylate cyclase are not prerequisites for a cell to form bone in vivo. Finally, cells expressing the phenotype of differentiated osteoblasts, including osteocalcin synthesis, still have a multipotential differentiation capacity and form bone and cartilage in vivo.
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PMID:Establishment and characterization of two immortalized cell lines of the osteoblastic lineage. 188 24

In the platelet-rich plasma of rabbits, 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-5-methyl-3(2H)-pyridazinone (CI-930) inhibited platelet aggregation triggered by AA, U-46619, ADP, collagen and PAF, with the IC50 values of 0.91, 0.73, 2.12, 2.35 and 7.15 mumols/L, respectively. The inhibitory effect of CI-930 on AA-induced aggregation was potentiated by PGE1, an adenylate cyclase activator, and antagonized by SQ-22536, an adenylate cyclase inhibitor. The contents of cAMP in washed rabbit platelets were increased by CI-930 5-50 mumols/L. In the concentration range of 0.5-500 mumols/L, CI-930 reduced the synthesis of TXB2 by either washed rat or rabbit platelets or rat pleural neutrophils. At the same time, CI-930 induced a dose-dependent increase of PGE2, PGF2a, and PGD2 biosynthesis by rat platelets and had no significant influence on the formation of 6-keto-PGF1a by the neutrophils. It is showed that CI-930 is an anti-platelet agent with a wide-spectrum activity and its anti-aggregating action may be exerted by dual mechanisms, both increasing cAMP contents and selectively inhibiting TXA2 synthesis in platelets.
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PMID:Effects of CI-930, a novel phosphodiesterase III inhibitor, on platelet aggregation and arachidonic acid metabolism. 196 75

In this paper we examine the characteristics of human cytolytic T lymphocytes (CTL) generated in the presence of forskolin and PGE2. Forskolin and PGE2 suppressed the generation of class-I-specific CTL. The CTL generated in the presence of forskolin and PGE2 had different characteristics which included their ability to proliferate in response to the alloantigen and their lectin-mediated cytolytic activity. The CTL generated in the presence of forskolin had normal proliferative response to the alloantigen, whereas the CTL generated in the presence of PGE2 showed a suppressed proliferative ability to the alloantigen. The two groups of CTL were then tested for their activity in the process of lectin-dependent cell-mediated cytotoxicity. After the addition of PHA into the chromium release assay the CTL generated in the presence of forskolin normally lysed the nonspecific targets, whereas the CTL generated in the presence of PGE2 did not show the normal response in lysing the nonspecific targets. The results suggest that the cytolytic machinery was intact when the CTL were generated in the presence of forskolin but CTL were not able to either recognize or lyse the target cell. However, the CTL generated in the presence of PGE2 did not share the same characteristics as the CTL generated in the presence of forskolin because the CTL generated in the presence of PGE2 were unable to kill even in the presence of lectin. It appears that the inhibitory effects of forskolin were mediated by cAMP and not by its effects on the potassium channels because the 1,9-dideoxy derivative of forskolin which did not activate adenylate cyclase also did not suppress the generation of CTL. However, it was not established whether the diverse effects of PGE2 on the generation of CTL were mediated by cAMP-dependent, -independent or by both mechanisms.
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PMID:Forskolin and prostaglandin E2 regulate the generation of human cytolytic T lymphocytes. 197 71

The messenger role of Ca+2, cyclic nucleotides and inositol triphosphates in the stimulation of pepsinogen and mucous secretion were studied using isolated pig [correction of nug] gastric chief cells and guinea pig mucous cells, resp. Pepsinogen secretion was stimulated by agents either working at the postreceptor adenylate cyclase (AC) level (db-cAMP, forskolin) or after 12-o-tetradecanoyl-phorbol-13-acetate (TPA) stimulation of protein kinase C (PK C). Similar secretory effects were observed with histamine (H), carbachol (C) and cholecystokinin (CCK). [Ca-2] in was elevated by C and by CCK, but not by H in both types of cells. Like TPA, both C and CCK, but not H, stimulated the Ca+2-sensitive particulate PK C. H increased the activity of cAMP-dependent PK A. PGE2, C and CCK were found to increase inositol-1,4,5-triphosphate content in mucous cells. The findings indicate that two pathways of the regulation of pepsinogen and mucous secretion (AC-cAMP-PK C and phosphoinositol breakdown cascade) can act synergistically.
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PMID:[Secondary messengers in the hormonal regulation of the functional activity of the main and mucoid cells in the stomach]. 198 55

The inflammatory mediators PGE2, DC-PGI2 and histamine as well as the beta-adrenergic drugs isoprenaline and salbutamol increase intracellular cyclic AMP-concentrations whereas Platelet Activating Factor does not induce any change in adenyl cyclase activity of normal human alveolar macrophages. Functional H2-histaminergic and beta 2-adrenergic receptor-subtypes are coupled to macrophage adenyl cyclase.
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PMID:Adenyl cyclase activity in human alveolar macrophages. 198 62

Prostaglandin (PG) E2 receptor-adenylate cyclase system was studied in the kidney of 12-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) to evaluate the role of this system in hypertension. PGE2 receptors were determined by a radioligand binding method using [3H]-PGE2. Adenylate cyclase responses to PGE2, sodium fluoride (NaF) and forskolin were also measured. The concentration of PGE2 receptor was increased in SHR compared with WKY. PGE2- and NaF-stimulated adenylate cyclase activities were significantly lower in SHR than WKY. There was no significant difference in forskolin-stimulated adenylate cyclase activity between SHR and WKY. NaF activates the nucleotide binding regulatory protein (G-protein) and forskolin directly activates the catalytic unit. These results indicate that the activity of G-protein coupled with renal PGE2 receptors is deficient in SHR. This defect may contribute to the elevation of blood pressure, through sodium retention.
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PMID:Deficient activity of nucleotide binding regulatory protein coupled with PGE2 receptor in renal medulla of spontaneously hypertensive rats. 210 7

The present study uses various kinin agonists and antagonists to examine the cellular mechanisms of bradykinin's actions on intracellular calcium, prostaglandins, and adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in cultured arterial smooth muscle cells (casmc) obtained from rat mesenteric arteries. Exposure to bradykinin produced a rapid release of calcium (peak less than or equal to 20 s) from intracellular stores and an increase in prostaglandin (PG) E2 and cAMP production in casmc. Compared with bradykinin, the bradykinin B1-agonist [des-Arg9]BK produced only a small increase in intracellular calcium. The bradykinin-mediated increase in intracellular calcium was competitively blocked by the B2 receptor antagonist [D-Arg-O-Hyp3-Thi5,8-D-Phe7]BK (B4307) but not the B1-antagonist ([des-Arg9-Leu8]BK). In addition, the similarity of the dose-response curves for the bradykinin-mediated increase in Ca2+, PGE2, and cAMP (half-maximal stimulation of 12, 11, and 13 nM, respectively) and the ability of the B2-antagonist (B4307) to block each of these effects of bradykinin suggest that all three effects are mediated by the same bradykinin (B2) receptor. Further studies revealed that increases in intracellular calcium are necessary for the bradykinin-mediated increase in PGE2 formation and the subsequent PGE2-dependent formation of cAMP. Taken together, these results suggest that bradykinin acts via a B2-receptor on arterial smooth muscle cells to release calcium from intracellular stores, leading to increases in PGE2 production and the PGE2-dependent activation of adenylate cyclase.
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PMID:Effects of kinins on cultured arterial smooth muscle. 215 31

Exogenous PGE2 stimulation of adenylate cyclase (AC) in intact and enzymatically dissociated micromass cultures of mesenchymal cells derived from the distal tip of stage 25 chick limb buds was examined over a six day period of culture. Responsiveness to PGE2 was measured in both dissociated and intact cell layers in an effort to determine if an inhibitory interaction occurred between PGE2 receptors and the extracellular matrix synthesized by differentiating chondrocytes. PGE2 responsiveness was maximal in both dissociated and intact prechondrogenic mesenchyme after 24 hours in culture and declined significantly as chondrocyte differentiation occurred on days 3 and 6. Equivalent activation of AC activity by PGE2 at each time point examined was noted in both cell groups. In contrast to the decreased responsiveness of differentiating chondrocytes to PGE2, stimulation of AC by forskolin resulted in increased levels of activity in differentiating chondrocytes of both cell groups between days 3-6. The results of the present study demonstrate that the decline in PGE2 responsiveness of differentiating chondrocytes most likely involves specific changes in the PGE2 receptor complex and not in either the interaction of the receptor with extracellular matrix components or a reduction in the available pool of AC present.
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PMID:Responsiveness of adenylate cyclase to PGE2 and forskolin in isolated cells from micromass cultures of chick limb mesenchyme during chondrogenesis. 215 23


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