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)

The characteristics of the effects of catecholamines, prostaglandins, and adenosine on the adenosine 3',5'-monophosphate (cAMP) content of human astrocytoma cells are described. Catecholamines interact with a typical beta-adrenergic receptor, i.e., the order of potency of catecholamines is isoproterenol larger than or equal to epinephrine greater than norepinephrine greater than dopamine, and propranolol is an inhibitor but phentolamine is not. The prostaglandins interact with a receptor that recognized PGE-1, PGE-2, and PGA-1 but not PGF-2-alpha. The effects of PGE-1 are blocked by 7-oxa-13-prostynoic acid, indomethacin, and meclofenamic acid in a rapid, reversible manner. The cells contain another adenylate cyclase-linked receptor that recognizes adenosine and the adenine nucleotides but not guanosine, deoxyadenosine, or adenine. Theophylline and other methylxanthines are competitive inhibitors of the effect of adenosine. Each class of effector appears to stimulate adenylate cyclase by interacting with a structure-specific receptor. This follows from the observation that the effect of each class of agonists can be blocked selectively by the various inhibitors and is consistant with the observation that co-addition of different agonists results in additive effects on accumulation of cAMP. The magnitude of the effect of any of the classes of agonists can be influenced by a variety of factors, some of which may be related to the peculiarities of growth in culture: (1) The cells secrete cAMP into the medium, and the magnitude of this secretion for a given rise in intracellular cAMP is different for different agonists. (2) The exposure of the cells to catecholamines or prostaglandins leads to a loss of responsiveness to a subsequent challenge by the same agonist. The magnitude of the agonist-induced loss of responsiveness is dependent on the concentration of the agonist and the time of exposure. The process is at least partially agonist specific in that exposure of cells to isoproterenol can lead to greater than 90% loss in catecholamine responsiveness with less than 20% loss in responsiveness to prostaglandins. (3) The responsiveness of the cells also changes as a function of the age of the culture and as a function of cell density. (4) Finally, it can be demonstrated that cells maintained in culture for prolonged periods (months to years) may lose responsiveness to specific agonists while responsiveness to other agonists remains unchanges or actually increases. The advantages and disadvantages of the use of cells in culture for studies of the regulation of cAMP metabolism are discussed.
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PMID:Factors influencing the effect of hormones on the accumulation of cyclic AMP in cultured human astrocytoma cells. 16 56

A reproducible method for dissociation and culture of rat luteal cells is described. The concentration of LH required to produce half-maximal stimulation of progesterone secretion was 50 ng/ml. The effects of prostaglandin E(2) (PGE(2)) and prostaglandin F(2alpha) (PGF(2alpha)) on basal and luteinizing hormone (LH)-stimulated progesterone production were examined. Both prostaglandins stimulated basal progesterone production but PGE(2) was about twice as active, showing a 2-fold maximal stimulation at 0.75 muM. When either prostaglandin was incubated simultaneously with LH, a dose-dependent inhibition of progesterone secretion occurred; PGF(2alpha) was 4 times more active than PGE(2), showing 50% inhibition at a concentration of 40 x nM. Thus, both prostaglandins are more active as antagonists than as agonists of LH with respect to progesterone secretion. PGF(2alpha) also inhibited LH-stimulated adenylate cyclase activity and cyclic AMP accumulation. The block in progesterone secretion was reversed by addition of dibutyryl cyclic AMP (1 mM) but not by theophylline (5 mM) alone. These data and the finding that PGF(2alpha) did not affect the specific binding activity of the LH receptor in intact luteal cells indicate that the rapid action of prostaglandins in luteal cells is due to a block of LH-dependent production of cyclic AMP which results in a decrease in progesterone secretion.
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PMID:Mechanism of the rapid antigonadotropic action of prostaglandins in cultured luteal cells. 20 95

Prostaglandin (PG) D(2) is synthesized in platelets at concentrations which could inhibit aggregation via activation of adenylate cyclase. To more directly define platelet-PG interactions, a binding assay has been developed for platelet PG receptors with [(3)H]PGD(2) as ligand. [(3)H]PGD(2) binding to intact platelets was saturable and rapid with the ligand bound by 3 min at 20 degrees C. PG competed with the [(3)H]PGD(2) binding site with a potency series: PGD(2) (IC(50) = 0.08 muM) >> PGI(2) (IC(50) = 2 muM) > PGE(1) (IC(50) = 6 muM) > PGF(2alpha) (IC(50) = 8 muM). Scatchard analysis of binding data from six normal subjects showed a single class of binding sites with a dissociation constant (K(d)) of 53 nM and 210 binding sites per platelet. This PGD(2) receptor assay was then used to study platelets from five patients with myeloproliferative disorders (polycythemia vera, essential thrombocythemia, and chronic myelogenous leukemia), as over 90% of these patients have platelets resistant to the effects of PGD(2) on aggregation and adenylate cyclase activity (1978. Blood.52: 618-626.). In the presence of 50 nM [(3)H]PGD(2), the patients' platelets bound 7.1+/-2.9 fmol ligand/10(8) platelets compared with 15.1+/-1 fmol/10(8) platelets in normals, a decrease of 53% (P < 0.01). Scatchard analysis showed that the K(d) of [(3)H]PGD(2) binding (33 nM) was comparable to normal platelets, which indicates that the decreased PGD(2) binding in these platelets represented fewer receptors rather than altered affinity of the ligand for the binding site. The 53% decrease in [(3)H]PGD(2) binding correlated with a 48% decrease in PGD(2)-activated platelet adenylate cyclase. The characterization of the platelet PGD(2) binding site provides further direct evidence that there are at least two PG receptors on platelets, one for PGE(1) and PGI(2), and a separate receptor for PGD(2). Direct binding analysis will be a useful tool for studying the role of PG in regulating platelet function, as demonstrated by the selective loss of PGD(2) binding sites in patients with myeloproliferative disorders.
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PMID:Characterization of the platelet prostaglandin D2 receptor. Loss of prostaglandin D2 receptors in platelets of patients with myeloproliferative disorders. 22 13

The effect of alloxan, a known inhibitor of adenylate cyclase, on the levels of prostaglandins E and F was investigated in pregnant rats. Animals were treated intraluminally with alloxan in normal saline or alloxan plus cyclic-AMP in normal saline or normal saline alone on day 4 of pregnancy. The uteri were collected on days 5 and 6 of pregnancy and the prostaglandins E and F were extracted and measured by a radioimmunoassay technique. In the alloxan treated rats, a significant reduction in PGE and PGF levels was found on days 5 and 6 of pregnancy as compared to untreated control group, whereas in the alloxan plus cyclic-AMP treated group the levels of PGE and PGF were comparable to those of the untreated control group. These findings suggest a possible relationship between prostaglandins and cyclic-AMP in the process of implantation in rats.
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PMID:Relationship between prostaglandins and cyclic-AMP in the process of implantation in rats. 23 16

A significant stimulatory action of PGE1 on adenylate cyclase of the particulate membrane preparation of rat heart was observed at 1 X 10(-4) M. PGE1 caused a positive inotropic effect on isolated spontaneously beating rat atria 1 X (10(-5) M, and an increase in atrial cyclic AMP level at 1 X 10(-6) M. PGE2 stimulated the atrial but not the whole heart particulate adenylate cyclase. PGF 2alpha had no effect on these enzyme preparations. Our results suggest that: (i) The inotropic response of isolated spontaneously beating rat atria to PGE1 may be connected with an increase in cyclic AMP level; (ii) the effect of prostaglandins on heart in vivo must be indirect, because the concentrations needed to stimulate isolated atria and particulate adenylate cyclase were high, compared with the doses effective in vivo.
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PMID:Effects of prostaglandins on rat cardiac adenylate cyclase. 72 Mar 90

Goldfish preovulatory ovarian follicles (prior to germinal vesicle breakdown) were utilized for studies investigating the actions of activators of different signal transduction pathways on prostaglandin (PG) production. The protein kinase C (PKC) activators phorbol 12-myristate 13-acetate (PMA; 100-400 nM), 1-oleoyl-2-acetylglycerol (5 and 25 micrograms/ml), and 1,2-dioctanoylglycerol (10 and 50 micrograms/ml) stimulated PGE production; the inactive phorbol 4 alpha-phorbol didecanoate, which does not activate PKC, had no effect. Calcium ionophore A23187 (0.25-4.0 microM) stimulated PGE production and acted in a synergistic manner with activators of PKC. Although produced in lower amounts than PGE, PGF was stimulated by PMA and A23187. The direct activator of phospholipase A2, melittin (0.1-1.0 microM), stimulated a dose-related increase in PGE production, whereas chloroquine (100 microM), a putative inhibitor of phospholipase A2, blocked basal and PMA + A23187-stimulated PGE production. Several drugs known to elevate intracellular levels of cAMP including the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.1-1.0 mM), forskolin (10 microM), and dibutyryl cAMP (dbcAMP; 5 mM) attenuate PMA + A23187-stimulated PGE production. Melittin-stimulated production of PGE was inhibited by dbcAMP, suggesting that the action of cAMP was distal to the activation of phospholipase A2. In summary, these studies demonstrate that activation of PKC and elevation of intracellular calcium levels stimulate PG production, in part, through activation of phospholipase A2. The adenylate cyclase/cAMP signalling pathway is inhibitory to PG production by goldfish ovarian follicles.
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PMID:Multifactorial regulation of prostaglandin synthesis in preovulatory goldfish ovarian follicles. 131 82

Prostaglandins (PGs) are known to have effects on hepatic glucose metabolism. Some actions of PGs in intact liver systems may not involve PG effects directly at the level of the hepatocyte. To define the ability of structurally distinct prostaglandins to affect hepatocyte metabolism directly, the regulation of glycogenolysis was studied in hepatocytes isolated from male Sprague-Dawley rats. PGF and PGB2 inhibited glucagon-stimulated glycogenolysis in the hepatocyte system. Pinane thromboxane A2 (PTA2) and PGD2 had no effect on glucagon-stimulated glycogenolysis. Consistent with their inhibition of glucagon-stimulated glycogenolysis, PGF2 and PGF2 alpha inhibited glucagon-stimulated hepatocyte cyclic AMP accumulation. These actions of PGB2 and PGF2 alpha are identical with those previously reported for PGE2. Additionally, PGE2, PGF2 alpha and PGB2 inhibited glucagon-stimulated adenylate cyclase activity in purified hepatic plasma membranes. In contrast, PGF2 alpha, PGD2 and PTA2 were all without affect on basal rates of hepatocyte glycogenolysis or hepatocyte cyclic AMP content. PGE2 also inhibited glycogenolysis stimulated by the alpha-adrenergic agonist phenylephrine. Exogenous arachidonic acid was not able to reproduce the affects of PGE2 or PGF2 alpha on hepatocyte glycogenolysis, consistent with an extra-hepatocyte source of the prostaglandins in the intact liver. Thus PGE2 and PGF2 alpha act specifically to inhibit glucagon-stimulated adenylate cyclase activity. No prostaglandin tested was found to stimulate glycogenolysis. PGE2 and PGF2 alpha may represent intra-hepatic modulators of hepatocyte glucose metabolism.
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PMID:Structural specificity for prostaglandin effects on hepatocyte glycogenolysis. 215 11

Stimulation of adenylate cyclase by prostanoids in isolated glomerulus has been demonstrated previously suggesting the interaction of these lipids with specific receptors. In the present study, the presence and characteristics of these purported specific PGE receptors has been evaluated. Binding studies were performed with both [3H]PGE1 and [3H]PGE2 in isolated rat glomeruli obtained by standard sieving methods. Radioligand binding was demonstrated to be both reversible and saturable. The equilibrium dissociation constant (Kd) value for PGE2 was 14.3 nM and maximum number of receptor sites (Bmax) was 81.4 fmol/mg protein. Similar values were obtained for PGE1. Competitive binding studies performed with [3H]PGE1 in the presence of various prostanoids revealed a common binding site for PGE1, PGE2 and 16,16-dimethyl PGE2. The relative potency for displacement of [3H]PGE1 binding of various prostanoids was PGE1 = 16,16-dimethyl PGE2 = PGE2 much greater than T X B2 = PGD2 much greater than PGF 2 alpha greater than 6-keto-PGF 1 alpha. Hill plot analysis of both [3H]PGE1 and [3H]PGE2 binding studies showed a simple non-cooperative bimolecular interaction between PGE and a single receptor population. Finally, a dose-dependent stimulation of adenylate cyclase was noted with various concentrations of PGE1 in a membrane preparation derived from a similar glomeruli preparation. Thus the results of these studies provide evidence for the presence of specific PGE receptors in the rat glomerulus.
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PMID:Specific prostaglandin E2 binding sites in isolated rat glomeruli: evidence for glomerular PGE receptors. 286 41

Corpora lutea from sheep and cows as well as human and primates contain both large and small steroidogenic cells exhibiting distinct functional properties. Only the small cells seem to be able to respond in vitro to LH stimulation by raising their progesterone secretion. However, the entire progesterone secretion of the corpus luteum has been shown to be regulated in vivo by LH in the primate. The LH steroidogenic action involves the activation of membrane adenylate cyclase whose molecular mechanism has been elucidated. Then a rise in intracellular cyclic AMP induces phosphorylation by a cyclic AMP dependent protein kinase of steroidogenic protein targets which have not yet been completely identified. In sheep and cows, luteolysis is believed to be the consequence of a series of reciprocal interactions between the corpus luteum whose large cells secrete pulses of oxytocin in response to PGF2 alpha luteolysin and the endometrium which secretes pulses of PGF2 alpha in response to oxytocin. The secretion of endometrial PGF2 alpha can only begin after the induction of endometrial receptors by estradiol, from the preovulatory follicles. Similarly in women and primates luteolysis, which does not require the presence of the uterus, could be the consequence of local reciprocal paracrine interactions between luteal cells of different types. These interactions are likely to involve PGF2 alpha' oxytocin and estradiol. The biochemical mechanism responsible for the inhibition by PGF alpha of LH induced progesterone secretion in luteal cells could involve a stimulation in the cell membrane of protein kinase C and the rise of cytosolic Ca+.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Recent concepts concerning the corpus luteum]. 307 52

Epithelial and stromal cells were isolated from endometrium of cyclic heifers by enzymic dispersion. These cells exhibited specific morphological and functional properties. Epithelial cells appeared cuboidal or columnal and showed contact inhibition as they reached confluence. Stromal cells were fibroblast-like and enlarged at the time of confluence after which they overgrew in multiple layers. The presence of specific receptors for PGE-2 and beta-adrenergic catecholamines (isoproterenol) was estimated by activation of adenylate cyclase. Stromal cells had more adenylate cyclase activity (P less than 0.01) than did epithelial cells before (basal) and after stimulation with guanosine triphosphate (GTP) and PGE-2. However, epithelial cells were much more responsive to isoproterenol (P less than 0.01). Treatment of cultured cells with indomethacin to block PG synthesis increased the sensitivity and maximal response to PGE-2 in stromal (P less than 0.01) but not in epithelial (P greater than 0.1) cells. The latter result suggested autologous desensitization of the PGE-2 response resulting from synthesis of PGs in cultured cells. Both cell types synthesized PGs in culture: PGF-2 alpha was synthesized in greater quantity in epithelial than in stromal cells (P less than 0.05) while stromal cells synthesized more PGE-2 than did epithelial cells (P less than 0.001). Endometrial cells separated in this way should prove useful for study of their specific role in the processes of implantation and maternal recognition of pregnancy.
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PMID:Specific properties of epithelial and stromal cells from the endometrium of cows. 316 29


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