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)

The cyclic nucleotide phosphodiesterase of Dictyostelium discoideum functions to maintain the responsiveness of cells to the chemoattractant cAMP during the aggregation phase of development. We have prepared a cDNA library and have isolated clones which contain a portion of the 5' untranslated region and the entire coding and 3' untranslated portions of the cyclic nucleotide phosphodiesterase gene. The primary structure of the extracellular cyclic nucleotide phosphodiesterase precursor has been deduced from the nucleotide sequence. The molecule is composed of 452 amino acids and was calculated to have a molecular mass of 51,078 daltons. Forty-nine amino-terminal residues which contain a hydrophobic leader sequence are not present in the mature extracellular enzyme. Four potential asparagine-linked glycosylation sites were found within the phosphodiesterase. An amino acid sequence homology search revealed no closely related proteins. Phosphodiesterase mRNA levels are low in growing cells and first increase soon after the onset of development. The amount of transcript then decreases before rising in abundance to maximum levels during the terminal stages of cell aggregation and apical tip formation. During formation of the fruiting body, levels of phosphodiesterase mRNA decrease. Exposure of cells to cAMP increases the amount of phosphodiesterase mRNA. Increases of mRNA abundance are correlated with increases in enzyme activity, suggesting regulation at the level of transcription.
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PMID:Molecular cloning and developmental expression of the cyclic nucleotide phosphodiesterase gene of Dictyostelium discoideum. 302 65

High-affinity antibodies against calmodulin (CaM)-dependent cyclic nucleotide phosphodiesterase and protein phosphatase (calcineurin) were purified and characterized. Rabbit anti-phosphodiesterase antibody did not react with other phosphodiesterases or with the regulatory subunits of cAMP-dependent protein kinase. Affinity-purified goat anti-calcineurin antibody recognized both the 61-kDa catalytic subunit and the 18-kDa Ca2+-binding subunit of the phosphatase. Neither antibody reacted with CaM, several CaM-binding proteins (calmodulin-dependent protein kinase, myosin light chain kinase, fodrin), or other cytosolic proteins from brain. The antibodies were used to compare the cellular localization of these two CaM-dependent enzymes in rat brain. Both calcineurin and phosphodiesterase were found predominantly in nerve cells; however, phosphodiesterase was restricted to very specific neuronal populations. Phosphodiesterase was prominent in the somatic cytoplasm and dendrites of regional output neurons--e.g., cerebellar Purkinje cells and hippocampal and cortical pyramidal cells. The extensive and uniform staining in the dendrites was consistent with postsynaptic localization and suggested an important function for this enzyme in neurons that integrate multiple convergent inputs. Calcineurin was present in virtually all classes of neurons, with immunoreactivity confined primarily to cell bodies. Both diffuse cytoplasmic staining and characteristic punctate staining of cell bodies were observed; the latter suggested compartmentalization of calcineurin at or near the plasma membrane. The results of this study demonstrate that calcineurin and phosphodiesterase are differentially localized in the central nervous system. Thus, the expression and compartmentalization of CaM-binding proteins may be highly regulated and specific for particular differentiated nerve cell types.
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PMID:Differential localization of calmodulin-dependent enzymes in rat brain: evidence for selective expression of cyclic nucleotide phosphodiesterase in specific neurons. 302 62

The intact rat adipocyte was used to investigate the possibility of common intermediates in the insulin stimulation of cyclic AMP phosphodiesterase and the beta-adrenergic/adenosine regulation of adenylate cyclase. A five minute incubation of the isolated adipocytes with insulin produced a 50-100% increase in the phosphodiesterase activity found in the particulate fraction of homogenates. The insulin stimulation was not impaired by the presence of either agonist or antagonists of the inhibitory adenosine receptor which acts on adenylate cyclase. Phosphodiesterase activation by insulin was also observable above the level of stimulation produced by the beta-adrenergic agent isoproterenol and forskolin. The validity of the enzyme activity measurements was supported by measurements of the hormonal actions on cyclic AMP levels within the cells. Possible crossover between the adenylate cyclase and phosphodiesterase regulation systems at a post-receptor site was investigated using adipocytes exposed to bacterial toxins specific for the modification of guanine nucleotide binding proteins. Both cholera toxin, which irreversibly activates Gs and pertussis toxin which inactivates Gi caused some stimulation of the phosphodiesterase activity and suppressed activation by isoproterenol, but neither toxin prevented the insulin stimulation of cyclic AMP phosphodiesterase. These results suggest, while common components may participate in the beta-adrenergic stimulation of both adenylate cyclase and phosphodiesterase, the mechanism of insulin activation of the phosphodiesterase does not involve the components of adenylate cyclase regulation.
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PMID:Insulin stimulation of cyclic AMP phosphodiesterase is independent from the G-protein pathways involved in adenylate cyclase regulation. 304 Aug 18

There has been an active search recently for non-glycoside, non-sympathomimetic positive inotropic agents. Phosphodiesterase inhibitors inhibit the breakdown of cyclic AMP, leading to an increase in intracellular cAMP concentration, and can be expected to enhance the force of myocardial contraction. The methylxanthines exert such an action in vitro; the situation in vivo is more complex, due to their manyfold actions. Phosphodiesterase F-III is relatively specific for cAMP degradation; the new phosphodiesterase inhibitors may act specifically by inhibiting this enzyme. Phosphodiesterase inhibitors with combined inotropic and vasodilatory action include amrinone, which is no longer in widespread use due to its pronounced side-effects, milrinone, which is much better tolerated and has shown promising results in recent large-scale trials, and sulmazole which has been withdrawn due to toxic effects in rodents. Other drugs are still under investigation. Of importance is the relative role of the inotropic versus dilatory action of these drugs. A salutory effect on resting haemodynamics, does not necessarily imply improved exercise haemodynamics. The pharmacokinetic profile of these drugs is also of interest. The clinical benefits should be sustained and the side-effects should not outweigh the beneficial actions of these drugs.
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PMID:Non-receptor-mediated inotropic drugs. 304 98

The effect of insulin on cyclic nucleotide phosphodiesterase (PDE) in rat luteal cells was studied. Cells were obtained from PMSG/hCG primed rats and further incubated or not with insulin. The hormone produced an increase of enzyme activity after a 10 min incubation of intact cells. Maximal stimulation was achieved at 0.2 nM of insulin. Two peaks of cyclic nucleotide phosphodiesterase activity were resolved after chromatography of cell cytosolic extracts on DEAE-cellulose. These peaks (I and II) were active with cAMP as substrate but only peak I was active with cGMP. The enzyme activity of both peaks was increased in cells treated with insulin. Phosphodiesterase activity in the two peaks show two kinetic components for cAMP hydrolysis, one of high affinity (Km 2-4 microM) and the other of low affinity (47-56 microM). Treatment of the cells with insulin produced a 2 to 8 fold increase of the Vmax of these peaks. In addition after stimulation with insulin, the activation of peak I phosphodiesterase by calmodulin was less effective.
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PMID:Regulation by insulin of cyclic nucleotide phosphodiesterase (PDE) from rat luteal cells. 330 72

ATP or adenosine (1 mM) added to extracellular buffer abolished both chloroquine- and monensin-dependent accumulation of [125I]iodoinsulin in isolated rat adipocytes. The effects of ATP were not secondary to its conversion to adenosine and were mimicked by beta, gamma-methyleneadenosine 5'-triphosphate. ATP, but not adenosine, partially inhibited the binding of insulin to the cellular receptor. Neither ATP nor adenosine had any significant effect on both internalization of cell-bound insulin and externalization of the internalized hormone. The degradation of cell-bound insulin was reduced to a considerable extent by both 0.1 mM chloroquine and 5 mM ATP, to a lesser degree by 1 mM ATP, and not significantly by 1 or 5 mM adenosine. Physiologically, (a) 1 mM ATP had a strong, while 1 mM adenosine had a mild inhibitory effect on the insulin-stimulated glucose transport without affecting its basal activity, (b) both ATP and adenosine moderately stimulated basal as well as insulin-stimulated glycogen synthase, and (c) ATP, but not adenosine, transiently stimulated basal cAMP phosphodiesterase without affecting the insulin-stimulated enzyme. Phosphodiesterase in cells that had been exposed to ATP for 30 min was refractory to ATP added afresh, but not to insulin. These data suggest that (a) extracellular ATP may block the degradative pathway of insulin processing, (b) adenosine might render the ordinarily irreversible intracellular traffic of insulin reversible or modulate a pathway which is yet to be identified, (c) the previously reported effect of ATP on glycogen synthase may not involve phosphorylation, (d) ATP stimulates cAMP phosphodiesterase by a mechanism which is distinct from that of insulin, and (e) the degradative pathway of insulin processing may not be involved in the physiologic actions of the hormone on glycogen synthase and phosphodiesterase.
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PMID:Diversity in the effects of extracellular ATP and adenosine on the cellular processing and physiologic actions of insulin in rat adipocytes. 331 98

The inactivation of excited rhodopsin in the presence of ATP, rhodopsin kinase, and/or arrestin has been studied from its effect on the two subsequent steps in the light-induced enzymatic cascade: metarhodopsin II catalyzed activation of G-protein and G-protein-dependent activation of cGMP phosphodiesterase. The inactivation of G-protein (from light-scattering measurements) and that of phosphodiesterase (from measurements of cGMP hydrolysis) have been studied and compared in reconstituted systems containing various combinations of the proteins involved (rhodopsin, G-protein, phosphodiesterase, kinase, and arrestin). Our results show that rhodopsin kinase alone can terminate the activation of G-protein and that arrestin speeds up the process at a relative concentration similar to that reported in the rod (half-maximal effect at 50 nM for 4.4 microM rhodopsin). Measurements of rhodopsin phosphorylation under identical conditions show that in the presence of arrestin total metarhodopsin II inactivation is achieved when only 0.5-1.4 phosphates are bound per bleached rhodopsin, whereas in the absence of arrestin it requires binding of 12-16 phosphates per bleached rhodopsin. Phosphodiesterase activity can similarly be turned off by kinase, and the process is similarly accelerated by arrestin.
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PMID:Inactivation of photoexcited rhodopsin in retinal rods: the roles of rhodopsin kinase and 48-kDa protein (arrestin). 336 20

Venoms from 20 species of stinging Hymenoptera, including nine species of ants and nine species of social wasps, were quantitatively analyzed for the following enzymic activities: phospholipase A, hyaluronidase, lipase, esterase, protease, acid phosphatase, alkaline phosphatase and phosphodiesterase. Phospholipase and hyaluronidase were present in all the venoms, with activity levels generally higher among the wasps than the ants (P less than 0.05). Lipase was present in high activity in several social wasp venoms and one ant venom, in low levels in two other ant venoms and absent from four tested snake venoms. Two-carbon esterase activity was present in the venoms of five social wasps and one ant. Non-specific protease was present at very high activity levels in the venoms of an army ant species and was also present in the venoms of a social wasp and another ant. Acid phosphatase activity was present in eight of the nine ant venoms, but was essentially absent from all the social wasp venoms. Alkaline phosphatase activity was clearly detectable in the venoms of only two species of ants. Phosphodiesterase, an enzyme not previously detected in insect venoms, was present in the venoms of three closely related ant species. Venoms with generally high enzymic activities included those of Polistes infuscatus, Vespula (V.) squamosa and Pogonomyrmex badius; those with low activities included Dolichovespula maculata, Apoica pallens and Dasymutilla lepeletierii. The 20 venoms were ranked according to overall activity levels using the eight enzyme activities plus lethal, hemolytic and pain-inducing activities. They were also compared phylogenetically using these 11 activities.
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PMID:Comparative enzymology of venoms from stinging Hymenoptera. 354 39

2',5'-Oligo(A)synthetase (2-5A) and 2-phosphodiesterase were found in the L cells nuclei. In the cell nuclei 2-5A is 10-30 times higher, than in the cytoplasm. It is induced by interferon and depends on the cell growth state. 2-Phosphodiesterase activity has two pH optima of hydrolysis of 2-5A, namely 7.1, and 7.9 and decreases after interferon treatment of cells. Thus, interferon treatment of cells leads to an increase of the 2-5A level in cell nuclei. One of the possible pathways for 2-5A action in cell nuclei is the regulation of (ADP-ribose)transferase activity. Treatment of L cells with 2-5A (A2pA2pA) leads to activation of ADP-ribosylation of proteins by a factor of 1.5 in a concentration range of 10(-9)-10(-7) M, but more higher concentrations of 2-5A inhibit this process up to 60%. Treatment of cells with actinomycin D has no influence on 2-5A induced changes in protein ADP-ribosylation. This result is indicative for a new pathway of interferon action and 2-5A mediated regulation of cell metabolism.
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PMID:[Metabolism of oligoadenylates in cell nuclei and regulation of protein ADP-ribosylation]. 377 90

Using a number of drugs that increase cellular cAMP levels, alterations in the amount of cell surface fibronectin and other transformation parameters were studied in Chinese hamster ovary (CHO) cells. The drugs include db-cAMP, different methylxanthines (theophylline, aminophylline, methyl isobutyl xanthine (MIX), caffeine and theobromine), papaverine and cholera toxin. Methylxanthines that have a methyl group at the seventh position lack reverse transforming potential; those that lack a methyl group at the seventh position induced reverse transformation in CHO cells, causing an increase in surface fibronectin, cell substratum adhesive strength and anchorage dependence for growth. Further, as methyl xanthines are substituted in other positions different from the seventh position, the more efficient they become in restoring normal phenotypic properties; the later agents also induced low saturation density via a cytostatic state causing accumulation of cells in the S and G2 phases of the cycle in contrast to the G1 arrest of normal cells at low saturation density. db-cAMP and cholera toxin induced cell elongation but like caffeine and theobromine, did not induce surface fibronectin. The non-methylxanthine phosphodiesterase inhibitor papaverine induced neither cell elongation nor surface fibronectin but produced a cytostatic effect similar to aminophylline and MIX. These studies suggest that the reverse transformation properties fall into two groups: (a) Differentiation-related properties including cell morphology, parallel alignment and surface matrix fibronectin, etc.; (b) cell cycle-related properties-low saturation density, cell arrest at G1 phase and anchorage-dependent growth. Phosphodiesterase inhibitors reversibly eliminate indefinite division potential of CHO cells by inducing a cytostatic situation and not by inducing a G1-specific arrest.
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PMID:Reverse transformation of Chinese hamster ovary cells by methyl xanthines. Structure-function relationships. 609 Jan 84


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