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

The failure of certain adrenal tumors to respond to ACTH was investigated in vivo be administration of corticotropin-(1-24)-tetracosapeptide (ACTH1-24) and dexamethasone and in vitro by studying the binding properties of ACTH1-24 and prostaglandin E1 (PGE1) and their effect on adenylate cyclase activity of the tumors' crude membranes; in addition, in five cases the stimulation of cortisol production in isolated adrenal cells by both hormones and dibuttyryl cyclic adenosine 3',5'-monophosphate (cAMP) was also studied. The results obtained in 13 hormone-producing tumors of the human adrenal cortex, i.e. 10 carcinomas and 3 adenomas, were compared with those found in normal human adrenal glands. According to the adenylate cyclase responses to ACTH1-24 and PGE1, the tumors fall into different categories. In the first group are six rumors in which the adenylate cyclase was stimulated by both ACTH1-24 and PGE; in addition specific binding could be demonstrated for the two hormones in all six. The binding affinity for 125I-ACTH1-24 was found to be about 10 times higher than that for 125I-ACTH11-24. In the one tumor in which the experiment was performed, bound 125I-ACTH1-24 was displaced by ACTH1-10. These results are similar to the ones found in normal human adrenal preparations. For two rumors of the group in which ACTH did not increase steroidogenesis in vivo, the biochemical abnormality might be located beyond cAMP formation. A second group encompasses six tumors in which the steroidogenesis in vivo and the adenylate cyclase activity were insensitive to ACTH1-24 but in which the enzyme was stimulated by PGE1 and NaF. However, these preparations bound 125I-ACTH1-24 and 125I-ACTH11-24, the binding affinity being similar for both peptides but 10 times lower than the one found in normal adrenal cortex for 125I-ACTH1-24. In the only case of this group where it was tested, ACTH1-10 did not displace bound 125I-ACTH1-24. This result strongly suggests the possibility of a modification or a loss of the receptor site that binds the N-terminal sequency (1-10) of ACTH, the biologically active part of the molecule. In the last tumor, both PGE1 and ACTH were unable to stimulate adenylate cyclase activity and steroid production in a preparation of isolated adrenal cells, although steroidogenesis was stimulated by dibutyryl though steroidogenesis was stimulated by dibutyryl cAMP. No specific binding for PGE1 could be demonstrated. However, 125I-ACTH1-24 and 125I-ACTH11-24 were found to be bound to the tumor with the same affinity.
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PMID:ACTH and prostaglandin receptors in human adrenocortical tumors. Apparent modification of a specific component of the ACTH-binding site. 16 92

Prostaglandin E1 (PGE1) and cholera enterotoxin stimulate small-intestine mucosal adenylate cyclase and intestinal secretion of water and electrolytes. The previous suggestion that PGE may mediate cholera-toxin effects was explored in these studies. Closed rabbit jejunal loops were injected in vivo with cholera toxin and compared to similar loops in the same animal injected with buffer. Loop mucosal homogenates and intestinal secretions were analyzed by radioimmunoassay for cAMP and PGE concentrations. Cholera toxin produced significant increases in mucosal and intestinal fluid cAMP; however, there were no significant increases in PGE in the toxin-treated loops when compared to the control loops. In addition, there was no correlation between cAMP and PGE in the same samples. These studies indicate that cholera toxin stimulates intestinal cAMP anc secretion independent of PGE synthesis and provide evidence against a specific role for PGE in mediating cholera-toxin effects.
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PMID:Prostaglandin E in cholera toxin-induced intestinal secretion. Lack of an intermediary role. 17 82

Human astrocytoma cells (1321N1) exhibit adenylate cyclase activities coupled to independent receptors for catecholamines and prostaglandins of the E-series. Exposure of the cells to either norepinephrine or prostaglandin E1 (PGE1) results in an initial rapid accumulation of cyclic AMP but also results in a progressive loss of responsiveness of the cells to agonists. Initially, the desensitization is in large part agonist-specific. However, with continued exposure to high concentrations of norepinephrine, partial loss of responsiveness to PGE1 occurs, and vice versa. The mechanism underlying this phenomenon does not appear to involve inactivation of the effectors, formation of an inhibitory substance in the culture medium or an increase in the rate of excretion of cyclic AMP from the cell. Blockade of protein synthesis (85%) by 5 mug/ml cycloheximide did not change the rate or extent of desensitization. When desensitized cells were incubated in the presence of the effectors, responsiveness was essentially completely recovered with a t1/2 of 5-7 hr. Cycloheximide recovery reduced. Norepinephrine-induced desensitization to either norepinephrine or PGE1 was blocked by sotalol, a beta receptor blocking agent. Incubation of the cells with dibutyryl cyclic AMP caused desensitization to both norepinephrine and PGE). The results suggest that catecholamine-induced desensitization occurs as a result of interaction of the agonist with the same receptor that is linked to activation of adenylate cyclase. Cyclic AMP appears to mediate at least the non-specific aspect of agonist-induced desensitization.
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PMID:Regulation of adenosine 3':5'-monophosphate content of human astrocytoma cells: desensitization to catecholamines and prostaglandins. 18 25

The liberation of arachindonate in the thyroid occurs at the expense of two distinct pools of precursors. (1) the phosphatidylinositol through a process Ca2+-dependent and cyclic AMP-independent; and (2) the triglycerides by a cyclic AMP-dependent lipase, in which the involvement of cyclic AMP-dependent protein kinase has not yet been determined. The "PI pool" or "paracyclic AMP pool" is mobilized very rapidly by large doses of TSH but its physiological significance can be discussed. The "triglyceride pool" or "post-cyclic AMP pool" is mobilized more slowly by small doses of TSH and seems not to be implicated in the acute TSH stimulation of adenylate cyclase. The "post-cyclic AMP pool" of prostaglandins would be very important as third messenger or as "long-acting TSH hormone". Some recent works of Boeynaems and Van Sande (16) and Madaoui et al. (17) on the thyroid support this hypothesis, as aspirin or indomethacin inhibits DBc-AMP stimulation of glucose oxydation, iodine organification, or thyroid hormone secretion. On the other hand, in the absence of prostaglandin synthesis, TSH still stimulates the adenylate cyclase, which means that prostaglandins are not obligatory intermediates of hormonal action on cyclic AMP production. In conclusion, these results show a TSH action in the thyroid on the release of fatty acids, precursors of PG's, from their lipidic stores. Nevertheless, a second control step is not excluded in conversion of cyclic endoperoxide to PGE or PGFalpha.
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PMID:Stimulation by TSH of prostaglandin synthesis in pig thyroid. 18 42

In rat brain homogenate, opiates exert a dose-related inhibition of PGE-stimulated cyclic (AMP) formation. This effect is stereospecific and is correlated with agonist potency. Naloxone antagonizes heroid in a dose-related way, without, at effective concentrations, itself inhibiting PGE-stimulated cyclic AMP formation. In morphine-dependent rats, intracerebroventricular injection of cyclic AMP intensifies and of dibutyryl cyclic GMP diminishes precipitated abstinence effects. In naive rats, the xanthines, theophylline and 3-isobutyl-1-methylxanthine, produce a quasimorphine-abstinence syndrome that is readily suppressed by heroin and intensified by nalosone. In rat brain homogenate, these xanthines inhibit cyclic AMP phosphodiesterase. These findings are concistent with these views: (a) The opiates specifically inhibit an adenylate cyclase of morphine-sensitive neurons that is sensitive to stimulation by PGEs. (b) Opiate agonist action is associated with the lowering of a neuronal cyclic AMP. (c) Both the morphine-abstinence syndrome in dependent rats and the quasi-abstinence syndrome in naive rats are associated with a rise in this neuronal cyclic AMP. (d) There are two types of endogenous humoral mediator acting on morphine-sensitive neurons, one of which is morphine-like and the other antimorphine-like in action.
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PMID:Opiates, cyclic nucleotides, and xanthines. 19 53

Prostaglandins (PG) of the E series and catecholamines stimulate adenosine 3':5'-monophosphate (cAMP) formation in human astrocytoma cells (1321N1). These two classes of effectors activated adenylate cyclase upon interaction with different receptor systems. No evidence for a mediatory role for PG in the action of catecholamines was found. PG interacted with 1321N1 cells with an order of potency of PGE1 = PGE2 greater than PGA1 greater than PGF2 alpha. The effect of combinations of the various PG indicated that all efficacious PG interacted with a common receptor. 7-Oxa-13-prostynoic acid and indomethacin were shown to be competitive inhibitors of the effect of PGE1 with Ki values of 4 and 150 micron, respectively. These two compounds did not inhibit the effect of isoproterenol. Polyphloretin phosphate caused a complex pattern of inhibition of the effects of PGE1 and at higher concentrations also inhibited the effects of isoproterenol. The mefenamate class of nonsteroidal anti-inflammatory agents was found to inhibit the effects of PGE1 with a potency order of meclofenamic acid greater than flufenamic acid = mefenamic acid. The inhibitory action of meclofenamic acid was complex involving specific, but partial, insurmountable antagonism of PGE1 as well as competitive inhibition of PGE1 effects. At higher concentrations of meclofenamic acid a nonspecific inhibition of the effects of both PGE1 and isoproterenol was observed. These studies suggest that the inhibition by nonsteroidal anti-inflammatory agents of the physiological effects of PGE1 in animals may occur, at least in part, at the level of adenylate cyclase. The possibility that multiple classes of adenylate cyclase-linked PGE receptors might exist in nature is discussed.
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PMID:Stimulation of adenosine 3':5'-monophosphate formation by prostaglandins in human astrocytoma cells. Inhibition by nonsteroidal anti-inflammatory agents. 19 79

The effects of prostaglandin (PG) E1, E2, A1, F1alpha, F2alpha or D2 on the rat renal cortical, outer medullary and inner medullary adenylate cyclase-cyclic AMP systems were examined. While high concentrations (8X10-4M) of each prostaglandin stimulated adenylate cyclase activity in each area of the kidney, PGE1 was the only prostaglandin to stimulate at 10-7M. PGA's were the only prostaglandins tested besides PGE's which stimulated adenylate cyclase at less than 10-4M. This effect of PGA's was limited to the outer medulla. PGD2 was the least stimulatory. Observations with renal slices yielded qualitatively similar results. The PGE's were the most potent in each area with PGA's only stimulatory in the outer medulla. O2 deprivation (5% O2) lowered the slice cyclic AMP content in each area of the kidney. In the cortex and outer medulla, prostaglandin mediated increases in cyclic AMP content were either lower or absent at 5% O2 compared to 95% O2. However, in the inner medulla PGE stimulation was observed only at 5% O2 and not 95% O2. No other prostaglandins were found to increase inner medullary cyclic AMP content at 95% or 5% O2. These results illustrate that the adenylate cyclase-cyclic AMP system responds uniquely to prostaglandins in each area of the kidney. Consideration of these results along with correlative observations suggests that inner medullary produced PGE's may act as local modulators of inner medullary adenylate cyclase.
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PMID:Effects of prostaglandins on rat renal adenylate cyclase-cyclic AMP systems. 19 51

The influence of steroid hormones on the response of human astrocytoma cells (1321N1) to prostaglandin E(1) (PGE(1)) has been investigated. Responsiveness to PGE(1) was determined by measuring the conversion of [(3)H]ATP to cyclic [(3)H]AMP in cells prelabeled with [(3)H]adenine. After incubation of the cells with dexamethasone, a marked increase in both the maximal effect (2- to 3-fold) and the potency (5-fold) of PGE(1) was observed. The effect was specific for the action of PGE(1) in that no change in the response of the cells to isoproterenol was observed. The EC(50) for dexamethasone was 0.001 muM and the effect was dependent on the presence of serum. The effect of dexamethasone was first observed after a 30- to 60-min lag and was maximal by 6-8 hr. Preconfluent cultures (3 days after seeding) exhibited optimal responsiveness to glucocorticoids. Both hydrocortisone and corticosterone mimicked the effect of dexamethasone but both were less potent. The action of dexamethasone was blocked by progesterone, testosterone, and 17alpha-methyltestosterone. Cycloheximide, at a concentration (1.0 mug/ml) that blocked protein synthesis (>90%) in 1321N1 cells, totally prevented the effect of dexamethasone on the response of the cells to PGE(1). Upon removal of dexamethasone from cells treated for 16 hr, responsiveness to PGE(1) returned to control levels with a half-time of 4 hr. Dexamethasone also was found to increase the response to PGE(1) of a Rous sarcoma virus-transformed human astrocytoma cell line and the WI-38 human fibroblast line. The most obvious interpretation of our findings is that glucocorticoids induce the synthesis of a protein that selectively modifies the sensitivity of adenylate cyclase to PGE(1).
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PMID:Glucocorticoids increase the responsiveness of cells in culture to prostaglandin E1. 20 Sep 33

Prostaglandins (PG) show different effects on the bronchomotoric excitability depending on the fact to which group they certain. The best investigated PG are PGE1, PGE2 (bronchodilators) and PGF2a (bronchoconstrictor). It is possible that PG play a certain role in the pathogenesis of bronchial asthma. Among other hypotheses, the influence upon adenylate cyclase - cAMP systems (without affecting the adrenoreceptors) is evident. Probably, PG exert a regulatory function on bronchial tone. The pathogenetic imporatnce of PG metabolites for bronchial asthma is discussed. A therapeutical influence upon bronchial asthma is theoretically possible on four ways: by 1) stimulation of partial endogenous synthesis of PGE, 2) inhibition of the biotransformation of PGE, 3) exogenous application of PGE, i.e. development of PGE derivatives indifferent to bronchial mucosa, stable in solution and relatively resistant to biotransformation and 4) inhibition of biosynthesis of PGF2a. The development of synthetic PGE1 derivatives (15-methyl-11-desoxy-PGE1) appears to be of future importance. Summarizing we can say that, at the present stage of development, a directed therapeutic utilization of PG for bronchial asthma seems to be of low probability yet. The problem of aspirin-induced asthma including all its practical consequences is discussed.
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PMID:[Prostaglandins and bronchial asthma (author's transl)]. 20 27


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