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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic AMP levels in primary monolayer cultures of epithelial cells prepared from mid-pregnant mice are stimulated by prostaglandin E1 and E2. Prostaglandin F1alpha and F2alpha have only a slight effect upon cyclic AMP levels. In the absence of phosphodiesterase inhibitors the rise in cyclic AMP produced by PGE1 is only transient and the levels return to normal within 30 minutes. High concentrations (16 mM) of theophylline are needed to prevent this decline, suggesting that the phosphodiesterase activity of epithelial cells in culture is high. However, theophylline alone produced only a small increase in basal cyclic AMP levels even over a 2-hour period indicating that basal cyclic AMP is turned over more slowly than cyclic AMP produced in response to stimulation with PGE1. Both PGE and PGF synthesis were monitored using radioimmunoassay procedures previously reported. The observed levels were found to decrease as cell density increased and were sensitive to the addition of agents such as collagen and naproxen.
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PMID:Prostaglandin biosynthesis and stimulation of cyclic AMP in primary monolayer cultures of epithelial cells from mouse mammary gland. 17 89

Human astrocytoma cells (1321N1) in culture respond to pharmacological concentrations of prostaglandins and catecholamines with a marked increase in the accumulation of cyclic AMP. However, growth of 1321N1 cells in the presence of low concentrations (0.003 to 0.1 muM) of prostaglandin E1 (PGE1) results in a marked reduction in the responsiveness of the cells-even to concentrations of PGE1 that normally stimulate maximal accumulation of cyclic AMP. Occasionally, a partial reduction in the responsiveness to catecholamines was observed in cells grown in the presence of PGE1. When it occurred this effect could be correlated with an increase in the cyclic AMP-degradation capacity of the cells. This loss of responsiveness to catecholamines could be completely reversed by 1-methyl-3-isobutylxanthine, a potent inhibitor of phosphodiesterase activity in 1321N1 cells. The consistently observed and more profound desensitization to the effects of PGE1 could not be correlated with an increase in cyclic AM-degradative capacity. Accordingly, 1-methyl-3-isobutylxanthine was only minimally effective in reversing desensitization to PGE1. It is concluded that the inability of 1321N1 cells grown in the presence of PGE1 to accumulate cyclic AMP upon subsequent challenge with PGE1 is primarily due to a selective desensitization of the PGE1-activated adenylate cyclase.
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PMID:Growth of astrocytoma cells in the presence of prostaglandin E1: effect on the regulation of cyclic AMP metabolism. 17 68

Thyroid cells from euthyroid patients with Graves' disease were cultured in a chemically defined medium. The cells preserved the ability to respond to TSH with 8-fold increase in cyclic AMP concentration. This cyclic AMP response to TSH was diminished by prior exposure of cells to TSH. The decrease in cyclic AMP response to TSH induced to TSH was reversible, was not associated with a similar decrease to cyclic AMP response to PGE1, and could not be attributed to increased phosphodiesterase activity or to decreased adenyl cyclase activity. The partial resistence to TSH stimulation of thyroid cells previously exposed to TSH may be due to changes in the TSH receptor, possibly caused by TSH itself.
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PMID:Cyclic AMP level of human thyroid cells in monolayer culture. TSH induced refractoriness to TSH action. 18 6

Possible differences of the mode of action of TSH and prostaglandin E1 (PGE) on the synthesis of cyclic AMP were studied in normal human thyroids (normal thyroid) and thyroids from thyrotoxic patients (toxic thyroid). TSH was less effective in toxic thyroids than in normal thyroids; whereas PGE1 was equally effective in normal thyroids and toxic thyroids. Since the basal level of cyclic AMP was the same in normal and toxic thyroids, this lower sensitivity of toxic thyroids to TSH was not due to the fact that toxic thyroids were already overactive in terms of cyclic AMP synthesis. The measurement of adenylate cyclase and phosphodiesterase activities in the plasma membranes or homogenates failed to explain this lower sensitivity of toxic thyroids to TSH. Small and large doses of T4 and T3 failed to suppress an increase of cyclic AMP produced by PGE1, in the slices and plasma membranes of normal and toxic thyroids; whereas large doses of T3 depressed an increase of cyclic AMP in response to TSH in the thyroid plasma membrane of toxic thyroids. When both TSH and PGE1 were administered simultaneously, an additive increase of cyclic AMP was found in normal thyroids and in toxic thyroids. From the data accumulated, we suggest that, although TSH and PGE1 stimulate cyclic AMP synthesis in normal and toxic thyroids, the site of action and/or mode of action of these two stimulators may possibly be different, at least in human thyroids.
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PMID:Comparison of prostaglandin E1 and TSH stimulation of cyclic AMP synthesis in thyroid tissues from euthyroid subjects and thyrotoxic patients. 18 93

Microwave irradiation is shown to be a useful method for simultaneously killing chicks and fixing tissues. Renal adenylate cyclase and phosphodiesterase activities were rapidly abolished by microwaving. The increase in chick kidney cyclic adenosine 3',5'-monophosphate (cyclic AMP) content produced by intravenous bovine parathyroid hormone (PTH) injection was much greater in microwaved birds than in those killed by cervical dislocation with subsequent tissue fixation in liquid nitrogen. After PTH injection there was a prolonged elevation of renal cyclic AMP content. At the time of maximum response (2 minutes), log. dose-response curves were linear in the dose range 0.1-10 U. The responses to three different bovine PTH preparations were indistinguishable. Arginine vasopressin, arginine vasotocin, salmon calcitonin and prostaglandin E1 did not affect kidney cyclic AMP content within 2 minutes. Because of its specificity and precision, the method is of use for the in vivo bioassay of PTH. Injection of CaCl2 (20 mumoles) 1 minute before, or conjointly with, bovine PTH inhibited the subsequent increase in kidney cyclic AMP content. The synthetic bovine PTH peptide fragments BPTH (1-34) and BPTH (2-34) both increased chick kidney cyclic AMP content. The use of such fragments allows investigation of the structural requirements of PTH for interaction with the systems regulating cyclic AMP metabolism in the kidney in vivo.
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PMID:Studies in vivo on the effects of parathyroid hormone upon kidney cyclic adenosine 3',5'-monophosphate content using rapid tissue fixation by microwave irradiation. 18 35

Our results indicate that indomethacin inhibits cyclic AMP phosphodiesterase in the myometrium of the pregnant rhesus monkey under in vitro as well as in vivo conditions. Kinetic data on extracts of myometrium from pregnant rhesus monkeys indicated two cyclic AMP phosphodiesterase activities. The apparent Km value for the high affinity enzyme averaged 3.9 muM and for the low affinity enzyme 23 muM; the Vmax values averaged 0.56 and 1.4 nmoles cyclic AMP hydrolized per mg protein min-1 respectively. When indomethacin was added to the myometrial extracts, the activity of the high Km phosphodiesterase was competitively inhibited, with an average Ki of 200 muM; the low Km enzyme was noncompetitively inhibited with an average Ki of 110 muM. Experiments on myometrial slices demonstrated that 10 muM indomethsacin potentiated the effect of PGE1 and epinephrine on cyclic AMP levels, presumably by inhibiting the phophodiesterase activity. The uterine relaxing effect of indomethacin is generally attributed to the inhibition of prostaglandin synthetase activity. However, treatment of pregnant rhesus monkeys with therapeutic doses of indomethacin resulted in a significant inhibition of myometrial cyclic AMP phosphodiesterase activity in association with uterine relaxation and prolongation of gestation.
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PMID:Effect of Indomethacin on cyclic AMP phosphodiesterase activity in myometrium from pregnant rhesus monkeys. 18 37

The mechanism underlying agonist-induced loss of responsiveness to catecholamines and prostaglandins has been investigated in human astrocytoma cells. Pulse-labeling of the cells with [3H] adenine during the time course of exposure to either norepinephrine or prostaglandin E1 (PGE1) demonstrated a reduction of the rate of incorporation of label into cyclic AMP within 5 min after exposure of the cells to either agonist. The loss of responsiveness observed by this technique was essentially agonist-specific during the first 30 min of exposure of the cells to either norepinephrine or PGE1. The rate constant for degradation of cyclic AMP throughout a 60 min exposure to either norepinephrine or PGE1 did not change suggesting that loss of responsiveness is not related to increased phosphodiesterase activity. The results are discussed in terms of a standard theoretical model for the regulation of the steady state level of an intermediate in a reaction sequence in which the rate of synthesis of the intermediate follows zero order kinetics and the rate of degradation follows first order kinetics. The hypothesis is put forth that agonist-induced desensitization is caused by an agonist-specific reduction in the rate of synthesis of cyclic AMP that follows rapidly after the initial stimulation of adenylate cyclase activity.
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PMID:Regulation of adenosine 3':5'-monophosphate content of human astrocytoma cells: mechanism of agonist-specific desensitization. 18 26

1. Sodium transport across isolated frog skin, as measured by the short-circuit current, was decreased by acetylsalicylic acid, mefenamic acid, paracetamol and phenylbutazone. Indomethacin (6 X 10(-6) M) had a biphasic effect on the short-circuit current: a transient increase followed by a sustained decrease. 2. The release of prostaglandin-like material from the skin was reduced by acetylsalicylic acid and indomethacin. Paracetamol caused a significant reduction in the short-circuit current response of the skin to low doses of arachidonic acid, but the response to the highest dose tested was not significantly altered. 3. Indomethacin (6 X 10(-6) M) increased the sensitivity of the skin to applied prostaglandin E1. The other prostaglandin synthetase inhibitors did not have this effect. Indomethacin (6 X 10(-6) M) also enhanced the effect of antidiuretic hormone on the short-circuit current. 4. Indomethacin (30 X 10(-6) M) increased the short-circuit current and diminished the response to applied prostaglandin E1. 5. In sulphate Ringer, theophylline increased the short-circuit current and diminished the response to prostaglandin E1. 6. Prostaglandin E1 increased the levels of cyclic AMP in frog skin and these increases preceded the increases in short-circuit current. There was a seasonal variation in the level of cyclic AMP in the skin: the levels in winter exceeded those in summer. There was also a seasonal variation in the cyclic AMP response to prostaglandin E1: the winter response was greater than that in summer. 7. Indomethacin (6 X 10(-6) M) had a biphasic effect on cyclic AMP levels in the skin, an initial increase followed by a decrease. Indomethacin also potentiated prostaglandin E1 stimulated cyclic AMP accumulation. 8. Theophylline increased cyclic AMP levels in the skin and potentiated prostaglandin E1 stimulated cyclic AMP accumulation. 9. Pre-treatment of the skin with theophylline reversed the effects of cyclic AMP on the short-circuit current and open-circuit potential. 10. It is concluded that endogenous prostaglandins help to maintain sodium transport across isolated frog skin and that the effects of E-type prostaglandins on the short-circuit current are mediated by increased cyclic AMP levels. The transient increase in short-circuit current and the increased skin sensitivity caused by indomethacin (6 X 10(-6) M) are attributed to inhibition of phosphodiesterase activity. The failure of theophylline to potentiate the short-circuit current response of the skin to prostaglandin E1 is attributed to alteration of cyclic AMP action on the skin by theophylline.
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PMID:Endogenous prostaglandins, adenosine 3':5'-monophosphate and sodium transport across isolated frog skin. 18 63

This research explored the possibility that cyclic nucleotides are part of the excitation-secretion sequence in mammalian motor nerve terminals. A series of reagents known to react with the enzymes that synthesize and degrade cyclic nucleotides or that are effectors of cyclic nucleotide actions were administered to in vivo cat soleus nerve-muscle preparations. The reagents were administered by rapid close intra-arterial injection while electrical activity in single motor axons and contractile activity of the muscle were monitored. NaF, an activator of adenylate cyclase, evoked bursts of action potentials in unstimulated axons and caused stimulus-bound repetitive activity in stimulated axons. It evoked vigorous asynchronous activity in the muscle and potentiated the force of muscle contraction. These effects are identical with those of cyclic N6-2'-O-dibutyryl adenosine 3':5'-monophosphate (dibutyryl cAMP). Prostaglandin E1 produced similar effects. Dithiobisnitrobenzoic acid and alloxan, inhibitors of adenylate cyclase, impaired neuromuscular transmission and prevented the effects of NaF, but they did not change the responses to dibutyryl cAMP. Theophylline, an inhibitor of phosphodiesterase, caused axons to respond repetitively to stimulation, but this activity had a different pattern from that produced by dibutyryl cAMP or NaF. Pretreatment with theophylline enhanced the responses to dibutyryl cAMP and NaF. Imidazole, an activator of phosphodiesterase, impaired neuromuscular transmission and prevented the effects of dibutyryl cAMP and NaF. Adenosine, an inhibitor of protein kinase, or verapamil, which inhibits calcium flux, impaired neuromuscular transmission and prevented the responses to dibutyryl cAMP, NaF and theophylline. These results are compatible with the hypothesis that cAMP is involved in the regulation of calcium flux and transmitter secretion in mammalian motor nerve terminals.
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PMID:A role of cyclic nucleotides in neuromuscular transmission. 18 85

The interaction of various spin-labeled compounds with the murine thymocyte adenylate cyclase-cyclic AMP system was investigated. Electron paramagnetic resonance spectra from spin-labeled compounds were used to calculate the order parameter, S, and indicated that the thymocyte plasma membrane is a relatively rigid structure. Increasing concentrations of spin-labeled stearates, but not their corresponding methyl esters, resulted in increased membrane fluidity, partial lysis, and concomitant complete inhibition of cholera toxin-mediated increases in cyclic AMP content. Upon subsequent isolation of plasma membranes from these cells, cholera toxin-stimulated adenylate cyclase activity was also completely inhibited. Direct addition of spin-labeled stearates, but not spin-labeled methyl stearates, to thymocyte homogenates caused a dramatic reduction of basal, cholera toxin-, isoproterenol-, NaF-, and prostaglandin E1-stimulated adenylate cyclase activity. Inhibition was complete within the first minute of addition to homogenates and required approximately 0.2 mM spin-labeled stearate I(12,3) for half-maximal inhibition. This inhibition occurred in the presence or absence of an ATP-regenerating system and was not readily reversible. Furthermore, since the membrane cyclic phosphodiesterase activity was not altered by spin-labeled stearates, their inhibition was attributed to a direct action of stearate spin labels on adenylate cyclase. Neither stearate, methyl stearate, spin-labeled methyl stearates nor 2,2,6,6,-tetramethylpiperidine-1-oxyl (Tempo) altered cell viability or enzyme activities at the concentrations studied. Spin-labeled stearates seemed to intercalate into different areas of the plasma membrane than their corresponding methyl esters. Furthermore, the action of spin-labeled stearates appeared to be on the exterior of the plasma membrane rather than the interior. These results illustrate the presence of multilipid domains and the importance of selected lipids and lipid-protein interactions in the adenylate cyclase-cyclic AMP system. Thymocyte adenylate cyclase is described in terms of a current model for membrane proteins.
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PMID:Spin-labeled stearates as probes for microenvironment of murine thymocyte adenylate cyclase-cyclic adenosine 3':5'-monophosphate system. 18 88


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