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)

Human monocytes in vitro respond to various agents (immune complexes, lectins, endotoxin, the divalent ionophore A 23187, 12-O-tetradecanoyl-phorbol 13-acetate [TPA], purified protein derivative [PPD] of Bacille Calmette-Guerin) with an increased synthesis of the protein component of thromboplastin. The effect of cyclic AMP and cyclic GMP on this response has been studied. Dibutyryl-cyclic AMP, prostaglandin E1 and the phosphodiesterase inhibitors 3-butyl-1-methyl-xanthine (MIX) and rac-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724), separately and in combination have a pronounced inhibitory effect on the response to immune complexes and PPD, and a moderate effect on the response to endotoxin and lectins. The effect on TPA response and on the response to A 23187 was slight. Dibutyryl-cyclic GMP (1 mM) gave a slight inhibition of the TPA and IC response, but had essentially no effect on the response to other inducers. The intracellular cAMP level increased when monocytes were incubated with IC, TPA or A 23187 followed by a decrease to basal levels within 1-2 hr, whereas lectin (PHA) and PPD did not induce such changes. The cAMP response to endotoxin varied. Stimulation with IC induced an increase in monocyte cGMP levels, whereas the other stimulants did not cause such changes.
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PMID:Effect of cyclic AMP and cyclic GMP on thromboplastin (factor III) synthesis in human monocytes in vitro. 632 Apr 87

Sperm surface changes during in vitro capacitation were examined with the help of an assay system using lectin-coated agarose beads. The nature and intensity of binding of epididymal spermatozoa to beads depended entirely on the particular stage of capacitation and the type of lectin attached to the bead surface. Fresh epididymal spermatozoa bound readily to beads coated with Con A, LCA, WGA, and PNA, but not with seven other lectins. During capacitation there was a constant decline in sperm binding to beads, and spermatozoa cultured for 4-5 hr bound only to those coated with Con A. A dramatic increase in sperm binding to Con A-coated agarose beads occurred between 4.5 and 5 hr, when large numbers of hyperactivated spermatozoa adhered, predominantly through their flagellae, to form large clumps on the beads. The clumping of spermatozoa on Con A-coated beads was enhanced in the presence of stimulators of capacitation (i.e., taurine, hypotaurine, and phosphodiesterase inhibitors) and was suppressed in the presence of various metabolic inhibitors (i.e., sodium azide and local anesthetics). The implications of these results are that the carbohydrate components of the entire surface of spermatozoa undergo striking changes during capacitation, and a close relationship may exist between the sperm surface and the metabolic changes occurring within capacitating spermatozoa. Sperm-bead binding assays are clearly able to recognize surface changes in asynchronous populations of motile spermatozoa and, due to their simplicity and speed, should prove to be valuable in gaining a greater understanding of the biochemistry of sperm capacitation.
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PMID:Lectin-coated agarose beads in the investigation of sperm capacitation in the hamster. 673 31

A small quantity of 125I-labeled human asialotransferrin type 3 (2 to 4 microgram/100 g) was injected in intact rats and the distribution of the hepatic radioactivity analyzed by fractionation of liver homogenates on continuous sucrose density gradient. The ligand rapidly partitioned between plasma membrane and the interior of the cell at an approximate ratio of 1 to 4. The ratio remained constant between 3 min and 1 h. Intracellular 125I was encapsulated in a particle that was of a median equilibrium density of 1.11 (1.109 to 1.114) g/cm3 at 20 degrees C. The ligand recovered from the particles showed no sign of proteolytic digestion and was bound by the immobilized asialoglycoprotein-binding lectin from rabbit liver. The electron microscopic appearance of the subfractions containing of the entrapped ligand closely resembled that of an intermediate Golgi preparation. Various attempts were made to separate the ligand-containing particles from sialyltransferase and phosphodiesterase I activities, but complete separation could not be accomplished. 125I-Asialoorosomucoid studied in the same quantities and under the same conditions as asialotransferrin, yielded a subcellular distribution which was distinct from that of asialotransferrin type 3. Increasing the dose of asialotransferrin, to a level at which rapid catabolism of this asialoprotein occurs, profoundly changed the subcellular distribution of radioactivity. The subcellular distribution thus obtained was comparable with that found for asialoorosomucoid. These findings suggest that asialotransferrin type 3 is associated with different intracellular vehicles (different endosomes?) depending on whether the protein is simply diacytosed or is en route to lysosomes.
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PMID:Subcellular distribution of human asialotransferrin type 3 in the rat liver. 728 66

Previous studies demonstrated that, upon attaining confluence, a clone of the renal epithelial cell, LLC-PK1, expressed progressively binding sites for the lectin Dolichos biflorus agglutinin (DBA) at the apical cell surface. Activation of cAMP-dependent protein kinase enhanced surface expression dramatically. The goal of this study was to define the process leading to surface expression of DBA binding sites and to investigate further the role of cAMP-dependent protein kinase in modulating surface expression. Both subconfluent and confluent cells exhibited intracellular DBA binding sites (50-70% of total cellular binding sites) in a perinuclear vesicular compartment which was disrupted by Brefeldin A treatment. Both total cellular content and the proportion of DBA binding sites at the cell surface increased modestly after confluence was attained. A 48 h treatment of cells with 1-methyl-3-isobutyl xanthine, a phosphodiesterase inhibitor, dramatically increased the level of cellular DBA binding sites as well as the proportion of DBA binding sites at the cell surface. Analysis of two mutants of this cell line suggests that the effect of 1-methyl-3-isobutyl xanthine requires cAMP-dependent protein kinase activity but is not due to cAMP-dependent protein kinase-mediated activation of gene transcription.
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PMID:cAMP-dependent protein kinase modulates expression and subcellular localization of Dolichos biflorus agglutinin binding sites in renal epithelial cells. 769 30

Several studies have shown the potential role of phosphatidic acid (PA) as a second messenger in different cell types. Thus, PA has been shown to mimic physiological agonists leading to various cellular responses, such as neurotransmitter and hormone release, cell proliferation by modulating DNA or RNA synthesis, the expression of several proto-oncogenes and growth factors, and the stimulation of enzyme activities such as phospholipase C (PLC), protein kinases and cyclic AMP (cAMP) phosphodiesterase. Stimulation of [3H]arachidonate-labelled rat thymocytes with the mitogen lectin concanavalin A (con A) resulted in enhanced production of radiolabelled PA after only 5 min of activation. The radiolabelled PA increase corresponded to a real increase in PA mass as determined by GLC quantification of its fatty acid content. In the presence of ethanol (0.5%), formation of phosphatidylethanol was not observed after 5 min of con A activation. Pretreatment of cells with R 59022 (10 microM), a diacylglycerol (DAG) kinase inhibitor, showed an inhibition in the formation of radiolabelled PA and in PA mass. These results suggest that the PLC-DAG kinase may be the pathway for PA synthesis in the first minutes of mitogenic thymocyte activation. A detailed analysis of the fatty acid composition showed that the relative amount of unsaturated fatty acids was increased in PA from stimulated cells concomitantly with a decrease in saturated ones; in particular, arachidonic acid was increased approximately 2-fold only 2 min after con A addition whereas palmitic acid was decreased for the whole period investigated (20 min). These changes favour the hydolysis of phosphoinositides rather than phosphatidylcholines by PLC. As PA remains a minor phospholipid, these changes are unlikely to affect cell membrane fluidity; but PA being now well recognized as a potential second messenger, its increased content as well as its increased unsaturation in the fatty acyl moiety might modulate several signalling pathways or the activity of enzymes such as cyclic nucleotide phosphodiesterase, controlling in this way the cellular level of cAMP, a negative regulator of blastic transformation.
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PMID:Time-course changes in content and fatty acid composition of phosphatidic acid from rat thymocytes during concanavalin A stimulation. 775 52

We have investigated the role played by cyclic nucleotide phosphodiesterases (EC 3.1.4.17) in the control of T-lymphocyte response to mitogenic agents by their ability to influence the cellular level of cAMP. The importance of this messenger as a negative regulator in this cell type is well established. Multiple isoenzymes of phosphodiesterase were fractionated from the cytosol of rat thymic lymphocytes by high performance liquid chromatography on an anion exchange column. In addition to the type II, III, IV isoforms that we have already described [Valette et al., Biochem. Biophys. Res. Commun. 169:864-872 (1990)], a phosphodiesterase fraction sharing several of the characteristics of type V, cGMP-binding phosphodiesterase, was detected. Non-isoform-selective inhibitors of phosphodiesterase such as dipyridamole, papaverine, and methyl-isobutylxanthine were able to totally prevent the proliferative response of thymocytes to stimulation by the mitogenic lectin concanavalin A. In contrast, the selective inhibitor of type IV phosphodiesterases rolipram induced a rather moderate inhibition of proliferation, not exceeding 60%; and the selective inhibitors of type III and type V phosphodiesterases, milrinone and M&B 22,948, respectively, displayed only marginal inhibitory effects. The association of the type III and IV phosphodiesterase inhibitors produced synergistic inhibition of proliferation, which could then be almost totally suppressed. These inhibitory effects on cell multiplication were reflected at the level of the cell cAMP content; only rolipram was able to induce a significant (approximately 50%) increase in cAMP, and this increase was potentiated by the presence of milrinone, reaching almost 100%. The type V phosphodiesterase selective inhibitor M&B 22,948 displayed similar properties to those of milrinone, which suggests that it indirectly inhibited the type III, cGMP-inhibitable isoenzyme, by inducing a cGMP rise. This hypothesis was supported by evidence of a significant raising effect of M&B 22,948 on cGMP level, and by the ability of a cGMP-elevating agent, sodium nitroprusside, to mimic the synergistic effects of milrinone associated with rolipram. Furthermore, 8-bromo-cGMP, a potent activator of cGMP-dependent protein kinase, which showed only weak inhibitory effects on thymic type III phosphodiesterase, failed to alter the effects of rolipram on the cell proliferation. These results allow us to delineate a role for types III, IV, and V phosphodiesterase in the control of cAMP level during the proliferative response of thymic lymphocytes. They also suggest that endogenously formed cGMP might participate in the regulation of cAMP level in the cells by means of the inhibition of the type III phosphodiesterase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Modulation of rat thymocyte proliferative response through the inhibition of different cyclic nucleotide phosphodiesterase isoforms by means of selective inhibitors and cGMP-elevating agents. 824 5

Several drugs have been used to stimulate human sperm motility, including 3-deoxy-adenosine, caffeine, and pentoxifylline. Pentoxifylline is an inhibitor of the phosphodiesterase and may stimulate sperm motility by increasing the intracellular levels of cAMP. In this study we have evaluated the effect of pentoxifylline in the outcome of the sperm penetration assay into zona-free hamster oocytes. Twenty-seven semen samples, obtained for diagnostic purposes, were used. After the motile sperm were selected by the swim-up technique, the samples were divided into two aliquots. One aliquot was incubated with 1 mg ml-1 of pentoxifylline at 37 degrees C, 5% CO2 for 30 min. The control aliquot was incubated with culture medium. The samples were then washed and resuspended in fresh, pentoxifylline-free medium, at a sperm concentration of 10 x 10(6) cells ml-1. One hundred microlitres of each sperm suspension was then deposited under oil and 30-40 zona-free hamster oocytes were added. After 6 h of gamete coincubation, the percentage of penetrated oocytes and the number of decondensed sperm heads were evaluated. The percentage of acrosome-reacted sperm was evaluated using the Pisum sativum lectin. The percentage of zona-free hamster oocytes penetrated was increased after pentoxifylline-treatment. The percentage of acrosome reacted sperm and the number of decondensed sperm heads per egg were not different between the control and the pentoxifylline-treated groups. The results suggest that the beneficial effect of pentoxifylline upon the sperm cells is not mediated by stimulation of the acrosome reaction.
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PMID:Pentoxifylline increases sperm penetration into zona-free hamster oocytes without increasing the acrosome reaction. 827 10

Among the various immune abnormalities which characterize active sarcoidosis, a low proliferative response of peripheral blood lymphocytes to mitogenic lectins has long been observed. Since membrane-associated G-proteins are very likely to be crucial elements in lectin signal transduction, we investigated the binding of 5'-guanylylimidodiphosphate (GppNHp), a non hydrolyzable GTP analogue, to blood total lymphocyte membranes and to blood T-lymphocyte membranes from patients with active sarcoidosis, and from healthy control subjects. GppNHp binding was markedly decreased in peripheral cells from patients with sarcoidosis as compared to controls, suggesting the occurrence of a defect at the level of G-protein(s). A further characterization of G-proteins in these cells by means of ADP-ribose-labelling in the presence of bacterial toxins brought forward a significant decrease in the labelling of a 40 kDa protein, the major pertussis toxin substrate, in membranes from sarcoid patients, while the labelling of the major 44 kDa cholera toxin substrate proved to be unchanged with respect to control membranes. It is hypothesized that, in sarcoid lymphocytes, a defect in the negative control of adenylate cyclase mediated by the inhibitory G-protein Gi, prevents the lowering of cAMP necessary to normal mitogenic response of blood lymphocytes to stimulation. cAMP degradation by the specialized enzyme phosphodiesterase constitutes another critical step in the control of cAMP levels. Both cAMP and cGMP phosphodiesterase activities were found decreased in blood total lymphocyte preparations from sarcoid patients. With purified T-cells, although the mean cAMP and cGMP phosphodiesterase activities from sarcoid patients were found more markedly decreased with respect to healthy donors, only the decrease in cGMP phosphodiesterase was found statistically significant. The role these defects in cyclic nucleotide degradation potentially play in the disturbance of blood lymphocytes response associated with sarcoidosis is discussed.
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PMID:Impaired G-proteins and cyclic nucleotide phosphodiesterase activity in T-lymphocytes from patients with sarcoidosis. 838 56

In this study, human spermatozoa obtained from donors (n = 15) with normal semen characteristics were cryopreserved in human sperm preservation medium, supplemented with the phosphodiesterase inhibitor pentoxifylline at concentrations of 0, 1, 3 and 10 mM. The effect of pentoxifylline on cryopreserved spermatozoa was determined by monitoring changes in sperm motility and acrosome morphology by labelling the spermatozoa with fluorescein-conjugated concanavalin A lectin. Cryoprotectant supplemented with 1 mM pentoxifylline was found to improve post-thaw progressive motility from 15.3 +/- 2.4 (control) to 23.1 +/- 3.8% (P < 0.01), and total motility from 27.4 +/- 3.3 (control) to 38.2 +/- 3.9% (P < 0.05) without reducing the percentage of spermatozoa with normal acrosomal regions, and so appears useful for cryopreservation purposes. The beneficial effects of 1 mM pentoxifylline on sperm motility were shown to be maintained post-thaw over a 6 h time course. Cryoprotectant supplemented with 3 mM pentoxifylline was found to improve only post-thaw progressive motility, from 15.3 +/- 2.4 (control) to 20.7 +/- 3.0% (P < 0.05). However, cryopreservation in the presence of 10 mM pentoxifylline was found to have a significantly (P < 0.01) detrimental effect on acrosome morphology post-thaw, reducing it from 29.0 +/- 2.0 (control) to 21.0 +/- 2.4% without affecting sperm motility. This suggests that assessment of the acrosomal region may indicate subtle deleterious effects of cryoprotectant supplements that cannot be determined from post-thaw motility assessments alone. These findings differ from previous studies in that a lower concentration of pentoxifylline (1 mM) was found to be optimal for cryopreservation purposes.
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PMID:Pentoxifylline-supplemented cryoprotectant improves human sperm motility after cryopreservation. 853 Jun 58

We have previously shown that mitogenic activation of human PBMC rapidly increases both the intracellular phosphatidic acid (PA) level and cyclic nucleotide phosphodiesterase (PDE) activity, with time-course responses, suggesting a causative relationship between the two events. PA also directly stimulated cAMP-PDE activity in acellular systems. Thus the mitogenic properties of PA night be due to its ability to lower the level of cAMP, a negative effector of lymphocyte activation, through PDE activation. In this study, human PBMC were stimulated either with the mitogenic lectin ConA, the anti-CD3 mAb OKT3, or the phorbol ester TPA. All three agonists increased the radiolabeled PA level and the PA mass in treated cells and simultaneously increased cytosolic and particulate cAMP- and cGMP-PDE activities, with significant positive correlations between PA accumulation and PDE activities. Furthermore, the ConA-induced PDE activation was dose-dependently reduced by treatment of PBMC with the diacylglycerol-kinase inhibitor R59022. This compound also dose-dependently lowered the PA level and inhibited the proliferative response to ConA. In addition, TPA-induced PDE activation was totally abolished by ethanol, which strongly reduced PA accumulation in response to the phorbol ester. These data suggest that PA increase may be linked to mitogen-induced PDE activation. Experiments performed in the presence of rolipram indicated that ConA and TPA stimulated both the rolipram-sensitive PDE4 and the rolipram-insensitive PDE activities, OKT3 being more active on PDE4. All three agonists stimulated the cGMP-specific PDE5. These results suggest that PA is an important component of the mechanisms that maintain a low level of cyclic nucleotides, which is a prerequisite for an optimal lymphoproliferative response.
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PMID:Relationships between phosphatidic acid and cyclic nucleotide phosphodiesterases in activated human blood mononuclear cells. 1008 May 43


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