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)

Hypercholesterolemia and hypertension are two of the major risk factors associated with increased atherosclerotic vascular disease. An abnormal platelet function is one of the mechanisms proposed to participate in atherogenesis. This study was undertaken to find out whether hypercholesterolemia in hypertensive patients can change platelet lipid composition and reactivity. Twenty-nine untreated hypertensive patients were distributed into 3 age, body mass index and blood pressure-matched groups according to their plasma cholesterol levels (normal, borderline or elevated, group NC, BC and HC respectively). Their platelet lipid composition, cytosolic Ca2+ concentration, cyclic AMP content and aggregating response to ADP and collagen were determined. Platelet from group HC patients were characterized by reduced cyclic AMP content (evaluated in the presence and absence of a platelet phosphodiesterase inhibitor) and aggregating responses to ADP and collagen, increased palmitic acid content and decreased arachidonic, eicosapentaenoic and docosatetraenoic and pentaenoic acid content, resulting in a lowered polyunsaturated to saturated fatty acid ratio (P less than 0.001). In contrast, platelet cytosolic Ca2+ concentration, DPH steady-state anisotropy and cholesterol to phospholipid molar ratio were not significantly changed. This indicates that hypercholesterolemia is accompanied in hypertensive patients by marked changes in platelet fatty acid composition, cyclic AMP content and response to aggregating agents. These changes, which clearly differ from those induced by in vitro cholesterol loading, could reflect not only the balance between LDL and HDL stimulation but also an adaptation to hemodynamic perturbations.
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PMID:Biochemical and functional alterations associated with hypercholesterolemia in platelets from hypertensive patients. 132 32

In order to study the regulation of fatty acid oxidation in the heart, the effects of some phosphodiesterase III inhibitors, such as enoximone and milrinone, on the oxidation of [1-14C]palmitic acid, [1-14C]octanoic acid, and [2-14C]pyruvate were studied in adult rat myocytes. Enoximone and milrinone, at a concentration of 0.25 mM, increased palmitate oxidation significantly, by 70 and 40%, respectively. Also, enoximone increased octanoate oxidation by 45%. In contrast, pyruvate oxidation was decreased by 60% by enoximone. To investigate the effects of enoximone or milrinone on the pathway of fatty acid oxidation, their effects on the oxidation of either [1-14C]palmitoyl-CoA or [1-14C]palmitoylcarnitine were studied with rat heart homogenates. Neither enoximone nor milrinone had any effects on the oxidation of these compounds. Compounds known to elevate intracellular [Ca2+] or cyclic AMP, such as the calcium ionophore A23187, ionomycin, dibutyryl cyclic AMP, or isoproterenol, had no effect on palmitate oxidation. Enoximone, at a concentration of 0.25 mM, increased palmitate uptake by 40% in rat myocytes. These results suggest that enoximone and milrinone increase fatty acid oxidation in myocytes by increasing their cellular transport, and they also show the usefulness of these compounds as a tool to study the regulation of this vital pathway in heart.
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PMID:Stimulation of fatty acid oxidation by phosphodiesterase III inhibitors in rat myocytes. 171 92

2',3'-Cyclic nucleotide-3'-phosphodiesterase (CNP1 and CNP2 with Mr of 46,000 and 48,000, respectively) is the major enzyme of central nervous system myelin. It is associated with oligodendroglial plasma membrane and uncompacted myelin (myelin-like fraction), which are in contact with glial cytoplasm. Proteins of the myelin-like fraction were labeled with [3H]palmitic acid in brain slices from 17-day-old rats and immunoprecipitated with anti-CNP antiserum. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography of immunoprecipitated material revealed intense acylation of CNP1 and CNP2, and radioactivity was released by hydroxylamine. Palmitic acid was covalently bound to CNP because radioactivity was not removed by extraction of immunoprecipitated CNP with organic solvent or by boiling in sodium dodecyl sulfate and dithiothreitol. However, treatment of immunoprecipitated CNP with (a) hydroxylamine-released palmitohydroxamate and palmitic acid, (b) sodium borohydride-released hexadecanol, and (c) methanolic-KOH-released methyl palmitate. Synthesis, acylation, or transport of CNP was not affected by monensin or colchicine. However, acylation of CNP was inhibited 24-32% by cycloheximide. These results provide conclusive evidence that CNP1 and CNP2 are fatty acid acylated with palmitate through a thioester linkage and is posttranslationally modified sometime after synthesis.
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PMID:2',3'-cyclic nucleotide-3'-phosphodiesterase in the central nervous system is fatty-acylated by thioester linkage. 216 18

NAD kinase with increased sensitivity to calmodulin was purified from pea seedlings (Pisum sativum L., Willet Wonder). Assays for calmodulin based on the activities of NAD kinase, bovine brain cyclic nucleotide phosphodiesterase, and human erythrocyte Ca2+-ATPase were compared for their sensitivities to calmodulin and for their abilities to discriminate between calmodulins from different sources. The activities of the three enzymes were determined in the presence of various concentrations of calmodulins from human erythrocyte, bovine brain, sea pansy (Renilla reniformis), mung bean seed (Vigna radiata L. Wilczek), mushroom (Agaricus bisporus), and Tetrahymena pyriformis. The concentrations of calmodulin required for 50% activation of the NAD kinase (K0.5) ranged from 0.520 ng/ml for Tetrahymena to 2.20 ng/ml for bovine brain. The K0.5's ranged from 19.6 ng/ml for bovine brain calmodulin to 73.5 ng/ml for mushroom calmodulin for phosphodiesterase activation. The K0.5's for the activation of Ca2+-ATPase ranged from 36.3 ng/ml for erythrocyte calmodulin to 61.7 ng/ml for mushroom calmodulin. NAD kinase was not stimulated by phosphatidylcholine, phosphatidylserine, cardiolipin, or palmitoleic acid in the absence or presence of Ca2+. Palmitic acid had a slightly stimulatory effect in the presence of Ca2+ (10% of maximum), but no effect in the absence of Ca2+. Palmitoleic acid inhibited the calmodulin-stimulated activity by 50%. Both the NAD kinase assay and radioimmunoassay were able to detect calmodulin in extracts containing low concentrations of calmodulin. Estimates of calmodulin contents of crude homogenates determined by the NAD kinase assay were consistent with amounts obtained by various purification procedures.
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PMID:An enzymatic assay for calmodulins based on plant NAD kinase activity. 609 19

The effects of various lipids on calmodulin interaction with Ca-dependent phosphodiesterase were investigated. Palmitic, myristic and stearic acids increased the enzyme activity; the degree of the enzyme activation by calmodulin was decreased thereby. Oleic acid produced a weak activating effect on phosphodiesterase but completely blocked calmodulin action. The effects of the fatty acids under study were reversible, the activation constant was equal to 10(-4)-5 X 10(-4) M. In the presence of Ca2+ phosphoinositides and fatty acids changed the fluorescence intensity of dansyl-labelled calmodulin; in the absence of Ca2+ the lipids did not affect protein fluorescence. The lipids had no influence on the protein affinity for Ca2+. During chromatography of phosphodiesterase on calmodulin-Sepharose the enzyme was eluted from the column both in the presence of EGTA and palmitic acid. It was concluded that fatty acids prevent the formation of the calmodulin - phosphodiesterase complex. This effects may both be due to the lipid binding to the enzyme and to calmodulin.
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PMID:[Effect of lipids on the binding of calmodulin with cyclic nucleotide phosphodiesterase]. 631 75

Rat spleen lymphocytes were incubated for 3 h with [14C]arachidonic acid in foetal calf serum. It was found that arachidonic acid distributed into phospholipids in the order phosphatidylcholine greater than phosphatidylethanolamine greater than phosphatidylinositol. After labelling with arachidonic acid the lymphocytes were washed, and incubated for up to 2 h with non-radioactive palmitic, oleic or linoleic acid dissolved in ethanol. The presence of ethanol or palmitic acid during a 2 h post-incubation had little effect on the amount of radioactivity found in different lipid fractions. Both oleic acid and linoleic acid, however, brought about an accumulation (up to 8-fold) of radioactivity in the diacylglycerol fraction. These fatty acids also brought about a change of radioactivity in several phospholipids, notably in phosphatidylinositol, which lost more than 50% of its counts during the 2 h incubation. Although maximum effects were seen at 2 h, diacylglycerol radioactivity was increased by 100% within 5 min after adding the fatty acids. The minimum concentration of fatty acids used (50 microM) gave an almost maximum response. The results indicate that unsaturated fatty acids may activate phosphatidylinositol phosphodiesterase in lymphocytes, as they do in brain. The possibility that a phospholipase A is activated is discussed. Possible implications for any experiments in which cells are incubated with fatty acids are pointed out.
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PMID:Formation of diacylglycerol and degradation of phosphatidylinositol induced in rat lymphocytes by non-esterified oleic or linoleic acid. 640 33

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

This study was designed to investigate the effects of the cardiovascular drug dipyridamole on fatty acid metabolism in isolated cardiac myocytes. Effects of dipyridamole on the oxidation of long-chain (palmitate) fatty acid, medium-chain (octanoate) fatty acid, and the carbohydrate intermediate (pyruvate) were determined by using isolated cardiac myocytes from both normal and diabetic rats. Dipyridamole increased palmitate oxidation in a concentration-dependent manner in both normal and diabetic myocytes. Maximal stimulation of palmitate oxidation (175% of control) was observed with 100 microM dipyridamole. In contrast, oxidation of octanoate and pyruvate was not affected. The stimulation of palmitate oxidation by dipyridamole persisted despite its removal from the incubation medium. In contrast to the effect in myocytes, palmitate oxidation was not affected by dipyridamole in isolated rat heart mitochondria. Palmitate uptake was increased by 2.5- and 1.6-fold when palmitate concentration was adjusted to 0.05 and 0.2 mM, respectively. Dipyridamole did not affect lipolysis in isolated myocytes. When dipyridamole (100 microM) and L-carnitine (5 mM) were added together to the incubation medium, palmitate oxidation was further increased to 223% of the control. The nucleoside transport inhibitor nitrobenzylthioinosine (NBMPR) failed to increase palmitate oxidation in isolated myocytes. Although palmitate oxidation in diabetic cells is much higher than that in normal myocytes, dipyridamole increased palmitate oxidation by 243% in diabetic myocytes over its baseline oxidation rate in normal cells. These results suggest that increased palmitate oxidation in isolated cardiac myocytes after dipyridamole administration occurs independent of effects on either the phosphodiesterase enzyme or nucleoside transport protein, but it may result from increased palmitate transport across the plasma membrane.
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PMID:Stimulation of long-chain fatty acid uptake by dipyridamole in isolated myocytes. 989 Mar 95

Phospholipase D (PLD) is a phosphodiesterase that catalyses hydrolysis of phosphatidylcholine to produce phosphatidic acid and choline. In the presence of ethanol, PLD also catalyses the formation of phosphatidylethanol, which is a unique characteristic of this enzyme. Muscarinic receptor-induced changes in the activity of PLD were investigated in porcine tracheal smooth muscle by measuring the formation of [3H]phosphatidic acid ([3H]PA) and [3H]phosphatidylethanol ([3H]PEth) after labeling the muscle strips with [3H]palmitic acid. The cholinergic receptor agonist acetylcholine (Ach) significantly but transiently increased formation of both [3H]PA and [3H]PEth in a concentration-dependent manner (>105-400% vs. controls in the presence of 10(-6) to 10(-4) M Ach) when pretreated with 100 mM ethanol. The Ach receptor-mediated increase in PLD activity was inhibited by atropine (10(-6) M), indicating that activation of PLD occurred via muscarinic receptors. Activation of protein kinase C (PKC) by phorbol-12-myristate-13-acetate (PMA) increased PLD activity that was effectively blocked by the PKC inhibitors calphostin C (10(-8) to 10(-6) M) and GFX (10(-8) to 10(-6) M). Ach-induced increases in PLD activity were also significantly, but incompletely, inhibited by both GFX and calphostin C. From the present data, we conclude that in tracheal smooth muscle, muscarinic acetylcholine receptor-induced PLD activation is transient in nature and coupled to these receptors via PKC. However, PKC activation is not solely responsible for Ach-induced activation of PLD in porcine tracheal smooth muscle.
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PMID:Activation of muscarinic receptors in porcine airway smooth muscle elicits a transient increase in phospholipase D activity. 1008 40

Spermatozoa undergo exocytosis in response to agonists that induce Ca2+ influx and, in turn, activation of phosphoinositidase C, phospholipase C, phospholipase A2, and cAMP formation. Since the role of cAMP downstream of Ca2+ influx is unknown, this study investigated whether cAMP modulates phospholipase C or phospholipase A2 using a ram sperm model stimulated with A23187 and Ca2+. Exposure to dibutyryl-cAMP, phosphodiesterase inhibitors or forskolin resulted in enhancement of exocytosis. However, the effect was not due to stimulation of phospholipase C or phospholipase A2: in spermatozoa prelabelled with [3H]palmitic acid or [14C]arachidonic acid, these reagents did not enhance [3H]diacylglycerol formation or [14C]arachidonic acid release. Spermatozoa were treated with the phospholipase A2 inhibitor aristolochic acid, and dibutyryl-cAMP to test whether cAMP acts downstream of phospholipase A2. Under these conditions, exocytosis did not occur in response to A23187 and Ca2+. However, inclusion of dibutyryl-cAMP and the phospholipase A2 metabolite lysophosphatidylcholine did result in exocytosis (at an extent similar to that seen when cells were treated with A23187/Ca2+ and without the inhibitor). Inclusion of lysophosphatidylcholine alone, without dibutyryl-cAMP, enhanced exocytosis to a lesser extent, demonstrating that cAMP requires a phospholipase A2 metabolite to stimulate the final stages of exocytosis. These results indicate that cAMP may act downstream of phospholipase A2, exerting a regulatory role in the exocytosis triggered by physiological agonists.
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PMID:Stimulation of Ca(2+)-dependent exocytosis of the sperm acrosome by cAMP acting downstream of phospholipase A2. 1079 26


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