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)

Isolated fat cells from rat epididymal adipose tissue were incubated with various lipolytic hormones in the absence and presence of the alpha-adrenergic blocking agent phentolamine. Lipolysis, stimulated by noradrenaline, isoproterenol, or ACTH, was inhibited dose-dependently by phentolamine. At concentrations of phentolamine where lipolysis was already inhibited, phentolamine had a biphasic effect on hormone-stimulated formation of cAMP. Low concentrations of phentolamine enhanced cAMP formation, while high concentrations inhibited cAMP. The additional increase of cAMP formation by phentolamine was only seen with maximally effective concentrations of noradrenaline, isoproterenol, and ACTH. Half-maximally effective concentrations were invariably inhibited by phentolamine. The activity of noradrenaline-stimulated adenylate cyclase of fat-cell plasma membranes was inhibited by phentolamine, whereas cAMP phosphodiesterase activity was unaffected.
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PMID:Biphasic effect of the alpha-adrenolytic phentolamine on hormone-stimulated formation of cyclic adenosine-3',5'-monophosphate in isolated fat cells of rats. 16 51

Cultured human epidermoid carcinoma (HEp-2) cells were found to contain a highly responsive, catecholamine-sensitive adenyl cyclase activity in cellfree preparations. By contrast, cyclic AMP levels in intact HEp-2 cells were at best only marginally increased by catecholamines under a variety of conditions. The lack of an intact cell response could not be accounted for by escape of cyclic AMP to the medium, excessive phosphodiesterase activity, inactivation of the catecholamine, or by unusual kinetics of the system. However, in the presence of 1-methyl,3-iso-butylxanthine (MIX), a potent phosphodiesterase inhibitor, a moderate catecholamine response was observed in the intact cells. A significant elevation of cyclic AMP levels in the presence of MIX was observed at 0.3 muM epinephrine, and maximal levels occurred at 10 muM. Norepinephrine was much less effective than either epinephrine or isopropylnorepinephrine at 10 muM concentrations. In addition, intact cells slowly but steadily released cyclic AMP into the incubation medium over the course of 60-min incubations in the presence of MIX and epinephrine; maximum intracellular levels were reached by 5 min.
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PMID:Studies on cyclic AMP metabolism in human epidermoid carcinoma (HEp-2) cells. 16 57

We have utilized dark field microscopy to observe the surface microstructure of living cultured cells. Using this method, we have found that dibutyryl cAMP treatment causes regression of the numerous, long cell surface microvilli present on L929 cells. Thirty minutes after removal of dibutyryl cAMP, microvilli reappear. An inhibitor of phosphodiesterase (methylisobutylxanthine) and a stimulator of adenylate cyclase (prostaglandin E1), both of which raise cAMP levels, cause regression of microvilli in 15 min. Untransformed 3T3 cells show very few microvilli when viewed still attached to their substratum or after removal with EDTA. Treatment of these cells with trypsin causes the formation of numerous microvilli on their surface. When clumps of cells agglutinated by concanavalin A are examined by thin section electron microscopy, the cells are seen to be held together by a "forest" of interdigitating microvilli and only rarely is there apposition of the areas of membrane between microvilli. At the same time the distribution of surface-bound concanavalin A was examined using immunofluorescent light microscopy, and concanavalin A was found to be uniformly distributed over the cell surface. We propose that agglutinability of mouse and rat fibroblasts is regulated through the modulation of cell surface microvilli by cAMP, and that transformed cells are highly agglutinable because their low cAMP levels result in the formation of numerous surface microvilli.
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PMID:Cyclic AMP modulates microvillus formation and agglutinability in transformed and normal mouse fibroblasts. 16 1

The cyclic GMP level in the ductus deferens is elevated by acetylcholine, norepinephrine, KCl, and the phosphodiesterase inhibitor SC-2964. The presence of extracellular Ca++ is required for the effects of all of these agents on cyclic GMP levels. In addition, Ca++ appears to be an important factor for the basal turnover of cyclic GMP in this tissue, but it may be less important in other tissues. These observations have led us to the following working hypothesis (Fig. 5): The interactions of some hormones or neurotransmitters with membrane receptors secondarily increase cyclic GMP formation after primarily increasing the influx of extracellular Ca++ or changing the distribution of Ca++ among intracellular pools or compartments. However, in addition to this possibility, other hormonal effects on particulate and/or soluble guanylate cyclase that do not involve Ca++ mediation must also be considered. Some agents that are known to increase cyclic GMP in tissues have been reported in preliminary communications to activate cell-free preparations of guanylate cyclase (Amer and McKINNEY, 1973; White, Ignarro, and George, 1973), but these reports have not yet been confirmed by other laboratories. Secretin has been reported to stimulate guanylate cyclase activity from several tissues (Thompson, Johnson, Lavis, and Williams, 1974), but the significance of this report is unclear since secretin has not yet been shown to increase cyclic GMP levels in any tissue. Thus, although not convincingly established, some hormones may increase particulate guanylate cyclase activity in a manner similar to that by which hormones increase adenylate cyclase activity. Alternatively, some hormones may increase soluble guanylate cyclase activity with mediating factors other than Ca++ being involved, or hormone-receptor interaction at the plasma membrane could conceivably induce a dislocation and change in effective activity of a reversibly bound, membrane-associated guanylate cyclase. Elucidating which or how many of these possibilities are operative will require thorough study and understanding of the fundamental behavior and properties of soluble and particulate guanylate cyclase activities.
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PMID:Regulation of cyclic GMP levels in the ductus deferens of the rat. 16 75

Pharmacologic characterization of the neurotransmitter-sensitive cyclic AMP-second messenger systems of brain has proven to be a complex and difficult endeavor. At least two types of receptor appear to be involved in the mediation of the effects of NE on cyclic AMP content. One of these receptor systems appears to mediate the potentiation by NE of the effect of adenosine of cyclic AMP accumulation. The cellular heterogeneity of brain has retarded the determination of the mechanism underlying the synergistic interaction of catecholamines and adenosine. An attempt to use clonal cell lines to examine the action of NE and adenosine on cyclic AMP content has resulted in the demonstration that adenosine acts in a hormone-like fashion to stimulate adenylate cyclase activity. However, the studies did not shed light on the mechanism of synergism. An increasing number of reports are appearing which support the idea that the responsiveness of cells to neuronally released NE may involve adaptive changes in the responsiveness of the cyclic AMP-second messenger system which compensate for chronic over- or underproduction of the first messenger, NE. Evidence was presented that such a regulatory process may be operative in rat cerebral cortex. Our studies of catecholamine-induced loss of responsiveness in human astrocytoma cells have led us to the conclusion that the loss in the capacity of the cells to accumulate cyclic AMP is a result of a loss in the capacity to synthesize cyclic AMP. However, it is probable that different cells make use of different mechanisms (e.g., changes in phosphodiesterase activity) to regulate their ability to respond to hormones or neurotransmitters. The physiologic importance of this level of regulation of responsiveness to hormones is not known at this time.
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PMID:Regulation of cyclic AMP content in normal and malignant brain cells. 16 90

The concentration of cyclic AMP (cAMP) and its metabolites (5'-AMP and adenosine) as well as the adenyl cyclase, cAMP phosphodiesterase, and 5'-nucleotidase activities were determined in lymphocytes of thymus, spleen, and lymph nodes of control and protein-deficient rats. The values of these parameters, when expressed as per milligran DNA and as per 10-8 cells, but not always when expressed as per milligran protein, were much lower in the thymus as compared with the spleen and the lymph nodes in the control rats. The protein-deficient diet increased the nucleotide concentrations in the thymus and spleen lymphocytes on a per milligram DNA basis except those of thymic cAMP, which did not change. The same diet also increased the activities of the enzymes involved in the cAMP metabolism in thymic, splenic, and lymph node lymphocytes. Such a peculiarity could be related to the reduction of the mitotic activity of lymphocytes caused by protein deficiency since an inverse relationship has been reported between this activity and the synthesis of cAMP. On the other hand, it was noted that purified lymphocyte suspensions contained paradoxically higher amounts per cell of DNA, RNA, and protein in the thymus, spleen, and lymph nodes of protein-deficient rats as compared with those of the control rats. However, when the cell preparations were not purified, only the lymph node cells displayed a strong increase in their DNA content. Prolongation of the S phase of the cell cycle in these lymphocytes is suggested.
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PMID:Cyclic AMP metabolism and nucleic acid content in the lymphocytes of the thymus, spleen, and lymph nodes of protein-deficient rats. 16 50

Simple one step assay methods for adenylate cyclase (ATP pyrophosphate-lyase (cyclizing) EC 4.6.1.1) and cyclic nucleotide phosphodiesterases (3',5'-cyclic nucleotide 5'-nucleotidohydrolase EC 3.1.4.17) have been developed. [alpha-32-P] ATP is used as the substrate for adenylate cyclase. Acid-heat destruction of [32-P] ATP remaining after the cyclase reaction followed by Zn-Ba treatment quantitatively leaves cyclic [32-P] AMP in the supernatant essentially free from other 32-P-containing compounds. This assay method requires no corrections for recovery and routinely yields blank values less than 0.03 per cent. If higher sensitivity is desired, a simple 5 min alumina column step can be introduced into the procedure which quantitatively elutes cyclic [32-P] AMP directly into a liquid scintillation vial and lowers the blank values to less than 0.002 per cent. This method is rapid and easily performed, without sacrificing high reliability, specificity, or sensitivity. One step phosphodiesterase assays are easily accomplished using 32-P-labeled cyclic nucleotides as substrates. Descending paper chromatography of the reaction mixture on individual 2 cm wide paper strips gives a complete and quantitative separation of all possible products including [5'-32-P] AMP and [5'-32-P] GMP from their respective 32-P-labeled 3',5'-cyclic nucleotides in 1-2 h. The paper strips are cut, inserted in scintillation vials without scintillant and the 32-P-products determined by Cerenkov counting. Low blank values of less than 0.5 per cent and the use of high specific activity 32-P-labeled cyclic nucleotide substrates make this method the most reliable and most sensitive phosphodiesterase assay described to date. Because of the simplicity, specificity, and high sensitivity obtainable with these assay methods using 32-P-labeled substrates, we have also devised simple conditions for the preparation and purification of [alpha-32-P] ATP, cyclic [32-P] AMP and cyclic [32-P] GMP with specific activities in excess of 100 Ci/mmol. These high specific activity 32-Plabeled cyclic nucleotides are important for these new assay methods and are also useful to follow purification recovery of endogenous cyclic AMP and cyclic GMP from biological materials before protein binding or radioimmunological isotope displacement assays when performed in the femtomole range.
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PMID:Assay for adenylate cyclase and cyclic nucleotide phosphodiesterases and the preparation of high specific activity 32-P-labeled substrates. 16 81

Daily intraperitoneal injection of cadmium chloride (0.25 or 1 mg/kg) for 21 or 45 days into rats significantly stimulated the activities of hepatic pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1, 6-diphosphatase, and glucose-6-phosphatase, increased the concentrations of glucose and urea in the blood, and decreased the levels of glycogen in the liver. Whereas chronic cadmium treatment failed to alter adenosine-3',5'-monophosphate phosphodiesterase (phosphodiesterase) activity, the endogenous levels of cyclic AMP (cAMP) and the activity of basal- and fluoride-stimulated forms of hepatic adenylate cyclase (AC) were markedly increased in cadmium-injected animals. Treatment with the higher dose (1.0 mg/kg) of cadmium chloride for 45 days produced greater metabolic alterations in hepatic tissue than those seen with the lower dose (0.25 mg/kg) given for a shorter period of time (21 days). Discontinuation of cadmium administration for 14 days in rats previously injected with cadmium chloride (1 mg/kg per day) for 21 days, failed to reverse the observed changes in hepatic cAMP or carbohydrate metabolism. A similar persistence of metabolic alterations was noted in rats treated with cadmium (1 mg/kg per day) for 45 days and subsequently maintained without additional treatment for 28 days. Administration of an acute dose of cadmium chloride (60 mg/kg) decreased hepatic phosphodiesterase activity and glycogen content 1 h after the injection. In addition, acute cadmium exposure increased blood glucose, serum urea, and hepatic cAMP levels, and produced an augmentation of basal- and fluoride-activated AC. However, the activities of various hepatic gluconeogenic enzymes remained unaffected in animals given an acute dose of cadmium chloride (60 mg/kg). Data provide evidence that suggests that the gluconeogenic potential of liver is markedly enhanced following chronic exposure to cadmium and that the cadmium-induced changes in carbohydrate metabolism may be associated with an enhanced synthesis of cAMP. In addition, the present study shows that the cadmium-induced metabolic alterations persist even after the cessation of cadmium treatment for a period of 28 days.
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PMID:Response of hepatic carbohydrate and cyclic AMP metabolism to cadmium treatment in rats. 16 49

A vasopressin resistant urinary concentrating defect has been described in patients receiving lithium salt for affective disorders. For the pathogenic mechanism of the concentrating defect it has been postulated that lithium inhibits the vasopressin-dependent cyclic AMP system. However, the results of indirect studies on the lithium effect are equivocal. Therefore, the effect of lithium specifically on the vasopressin-dependent cyclic AMP system was investigated in rat renal medulla. The increase of cyclic AMP concentration by vasopressin was inhibited by lithium. But lithium had no effect on the PTH-dependent cyclic AMP concentration in renal cortical slices. Regardless of magnesium concentrations from 0-10 mM in the incubation media, 10 mM lithium had no moeasurable effect on the vasopressin-dependent adenylate cyclase of rat renal medulla. However, 10 mM lithium augmented the cyclic AMP-phosphodiesterase activity in renal medulla in the high Km system. These results suggest that lithium inhibits the vasopressin-dependent cyclic AMP concentration in renal medulla via the augmentation of its catabolism, rather than via the inhibition of cyclic AMP generation.
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PMID:Effects of lithium on vasopressin-dependent cyclic AMP in rat renal medulla. 16 28

We have perfused isolated rat livers with hypocalcemic (4.4 mg 100 ml) Krebs-Ringer bicarbonate albumin buffer. After 15 min of perfusion, a substance appeared in the perfusate which decreased rat renal adenylate cyclase activation by parathyroid hormone (PTH). The material in the perfusate was purified greater than 50,000-fold by Bio-Gel P-10 chromatography. The purified antagonist decreased the activation of rat renal cortical adenylate cyclase by PTH, glucagon, and epinephrine 75 to 100%. Concentration response curves for each of the hormones indicated a noncompetitive interaction of the inhibitor with the hormone. The inhibition was not species-specific, as the activation of the parathyroid hormone-responsive adenylate cyclase in cat renal cortex was also abolished by the inhibitor from the perfused rat liver. The inhibitor is a peptide, Mr equal to similar to 1000, which is heat-stable, acid-stable, alkai-labile, and is destroyed by trypsin, leucine aminopeptidase, and elastase. It is not destroyed by phosphodiesterase, 5'-nucleotidase, alkaline phosphatase, neuraminidase, RNase, or phospholipase A. The inhibitor is not produced by isolated rat livers perfused with normocalcemic perfusion media. It is unclear whether the peptide is synthesized by the liver or whether it is a breakdown product of a larger peptide or protein in the liver. This is the first reported peptide inhibitor of adenylate cyclase.
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PMID:Isolation of a unique peptide inhibitor of hormone-responsive adenylate cyclase. 16 24


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