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)

Carbenoxolone slightly but significantly decreased the release of FFA from rat epididymal fat pads. The antilipolytic action of carbenoxolone was not blocked by 10(-3)M 3-isobutyl-1-methylxanthine, a potent inhibitor of phosphodiesterase. The findings suggest that carbenoxolone exerts its antilipolytic activity by acting on adenylate cyclase, thereby decreasing cyclic AMP concentrations and the activity of the hormone-sensitive lipase in adipose tissue.
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PMID:Effect of carbenoxolone on lipolysis in rat adipose tissue. 2 44

When isolated rat epididymal fat cells were incubated with [125I]iodoinsulin for 5 min at 37 degrees, radioactivity accumulated in the plasma membrane fraction (Peak 1) and an unidentified particulate fraction (Peak 2) as reported previously (Kono, T., Robinson, F.W., and Sarver, J.A. (1975) J. Biol. Chem. 250, 7826-7835). This accumulation of radioactivity in Peak 2 (but not that in Peak 1) was greatly impaired when cells were incubated with iodoinsulin in the presence of a variety of metabolic inhibitors that reduce the cellular content of ATP. The reduction in the ATP level coincided with a disappearance of the stimulatory effects of insulin on sugar transport and the hormone-sensitive phosphodiesterase. In contrast, ATP depletion had no significant effects, at least during a 5-to 15-min incubation, on the intracellular water space and on the basal sugar transport and phosphodiesterase activities. When cells once depleted on ATP by treatment with 2,4-dinitrophenol (1 mM; 10 min) were washed and suspended in fresh buffer, the ATP level was recovered almost fully in 10 min. This recovery coincided with the restoration of responsiveness to insulin. When cells were incubated with [125I]iodoinsulin or insulin for 5 min at 15 degrees instead of 37 degrees, a negligible quantity of radioactivity accumulated in Peak 2 and insulin failed to activate sugar transport. In contrast, under the same conditions, radioactivity accumulated in Peak 1 and insulin stimulated phosphodiesterase considerably. These results suggest that ATP, or some other compound metabolically related to ATP, may be necessary for the actions of insulin on sugar transport and phosphodiesterase. ATP, or some other related compound, may also be necessary in the formation of the radioactive Peak 2, although the physiological function and cellular location of this peak are yet to be ascertained.
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PMID:Actions of insulin in fat cells. Effects of low temperature, uncouplers of oxidative phosphorylation, and respiratory inhibitors. 6 33

Evidence is presented that modulation of the maximum velocity of a particulate low K-m cyclic adenosine 3':5'-monophosphate (cyclic AMP) phosphodiesterase by thyroid hormones is one mechanism for the regulation of the responsiveness of rat epididymal adipocytes to lipolytic agents such as epinephrine and glucagon. Fat cells of propylthiouracil-induced hypothyroid rats are unresponsive to lipolytic agents and the V-max of particulate low K-m cyclic AMP phosphodiesterase of these cells is elevated above normal. In vivo treatment of hypothyroid rats with triiodothyronine restores to control values both the lipolytic response of the fat cells to epinephrine and the V-max of the particulate bound low K-m cyclic AMP phosphodiesterase. No similar correlation is found with the soluble high K-m cyclic AMP phosphodiesterase. The phosphodiesterases of fat cells from normal and hypothyroid rats respond identically in vitro to propylthiouracil, triiodothyronine, methylisobutylxanthine, or theophylline, although the particulate low K-m cyclic AMP phosphodiesterase is inhibited to a greater extent than soluble cyclic guanosine 3':5'-monophosphate phosphodiesterase activity. Protein kinase of fat cells from hypothyroid rats can be stimulated by cyclic AMP to the same total activity as observed in fat cells of normal rats. However, less of the protein kinase in fat cells from hypothyroid rats was in the cyclic AMP-independent form. This shift in the equilibrium of protein kinase forms is consistent with an increased activity of low K-m cyclic AMP phosphodiesterase and probably results from a lowering of the lipolytically significant pool of cyclic AMP.
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PMID:Cyclic nucleotide phosphodiesterases and thyroid hormones. 16 41

Quantitative studies of the action of theophylline and papaverine were performed in rat epididymal fat pads, both on the lipolytic effect and on the activity of phosphodiesterase, adenylate cyclase and protein kinase. Papaverine, a stronger inhibitor of phosphodiesterase than theophylline, did not produce lipolysis. The maximum lipolytic effect (glycerol release) of theophylline was much higher than that of epinephrine and nearly approached the effect exerted by dibutyryl cyclic AMP. While theophylline potentiated or was without any effect on lipolysis produced by epinephrine and dibutyryl cyclic AMP, papaverine at concentration 10- minus 3 M reduced the effect of both drugs as well as of theophylline by 90 per cent. These concentrations of papaverine also strongly inhibited the activity of adenylate cyclase. Neither papaverine nor theophylline prevented the activation of protein kinase by cyclic AMP. The data suggest that the lack of a lipolytic effect of papaverine migth be caused by a combination of its inhibitory effect on adenylate cyclase and direct inhibition of activation of triglyceride lipase.
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PMID:The absence of stimulation of lipolysis by papaverine, a strong inhibitor of phosphodiesterase. 16 81

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

Preincubation of isolated epididymal fat cells with dexamethasone or treating rats with cortisol enhances the epinephrine-stimulated lipolysis of the cells as well as cAMP-dependent protein kinase activity in homogenates of these fat cell suspensions. During maximal inhibition of phosphodiesterase activity by theophylline or dibutyryl cAMP, this potentiating effect of glucocorticoids on the fat cells was also present. There was no lowering of the total phosphodiesterase activity in homogenates of fat cell suspensions of rats that were treated with cortisol, but there appeared to be a lower activity of the low KM phosphodiesterase activity. It is concluded that induction of protein kinase by glucocorticoid hormone is responsible for its special type of stimulative action on lipolysis.
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PMID:The mechanism of the potentiating effect of glucocorticoids on catecholamine-induced lipolysis. 16 65

As it was shown previoulsy by others, the membrane-bound phosphodiesterase (cyclic adenosine 3':5'-monophosphate phosphodiesterase) of rat epididymal fat cells was stimulated when intact cells were exposed to insulin. The levels of stimulation observed in the present study in the cell homogenate and microsomal fraction were approximately 2.0- to 2.5-fold and 2.5- to 3.0-fold, respectively, when the initial substrate level was 100 nM and insulin concentration was 1 to 3 nM. When the microsomal fraction was subjected to a sucrose density gradient centrifugation, most of the insulin-sensitive phosphodiesterase activity was fractionated into the "light" microsomal fraction which was rich in NADH2:potassium ferricyanide:oxidoreductase) and low in 5'-AMPase, adenylate cyclase, and insulin-binding activities. The latter three activities were mostly fractionated into the "heavy" microsomal fraction. Both basal and insulin-stimulated phosphodiesterase activities were low when cells were homogenized in the presence of N-ethylmaleimide or p-chloromercuribenzoate. The insulin-stimulated enzyme activity was also low when cells were homogenized in the presence of --SH compounds (e.g. dithiothreitol) or certain metal-chelating agents (e.g. ethylene glycol bis(beta-aminoethyl ehter)-N,N'-tetraacetate (EGTA)), or in a nitrogen atmosphere. The effect of EGTA was prevented by the addition of certain heavy metal ions but not by the addition of Ca2+ or Ca2+ plus Mg2+ ions. When cells were homogenized in the presence of certain oxidants (e.g. diamide, sodium tetrathionate, or air), a high plus-insulin activity was observed; this activity was not lowered by subsequent treatment of the enzyme with N-ethylmaleimede, EGTA, or fresh cell homogenate that was prepared in the presence of EGTA. However, the activity of an apparently oxidized enzyme could still be lowered by treatment woth dithiothreitol. A partially purified enzyme in the enzyme in the microsomal fraction was fairly stable both in basal and insulin-stimulated states (fully active after 35 days when kept at -20degrees). EGTA added to the homogenization buffer lowered the basal phosphodiesterase activity, but this effect was reversed by the addition of Ca2+ ions. EGTA also decreased the enzyme activity that was stimulated by norepinephrine. However, neither EGTA nor dithiothreitol had any effect on the activities of 5'-AMPase, NADH-dehydrogenase, and malate dehydrogenase of fat cells. The above data indicate that most of the insulin-sensitive phosphodiesterase and the so-called "cell membrane markers" are associated with different subcellular particles in the cell homogenate. In addition, the data seem to indicate that the insulin-stimulated phosphodiesterase has certain --SH groups and that the activity of the enzyme is stabilized when the --SH groups are oxidized by certain oxidants including molecular oxygen. It is suggested that the air oxidation of the enzyme is catalyzed by a trace of certain heavy metal ions and, therefore, can be blocked by a metal-chelating agent.
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PMID:Insulin-sensitive phosphodiesterase. Its localization, hormonal stimulation, and oxidative stabilization. 17 Feb 71

Testicular and cauda epididymal sperm were obtained via catheters previously implanted in the rete testis and proximal vas deferens of bulls and were used to examine the relationships among sperm motility, cyclic adenosine 3':5'-monophosphate (cAMP) level, adenine nucleotide levels, and rates of glucose and oxygen consumption. Testicular, cauda epididymal, and ejaculated sperm contain cAMP-stimulated protein kinase, adenylate cyclase, and nucleotide phosphodiesterase. Treatment of the nonmotile testicular sperm with phosphodiesterase inhibitors resulted in a doubling of cellular cAMP concentration and a 25% increase in their glucose consumption. No change in motility, ATP level, or rate of oxygen consumption was observed. Sperm in neat cauda epididymal semen had flagellating tails but no progressive motility. Dilution of these sperm into glucose-containing buffer resulted in an increase in intracellular cAMP concentration and a decrease in ATP level with concomitant increases in ADP and AMP levels. These biochemical changes occurred within 30 s after dilution and apparently preceded the initiation of progressive motility by most cells. Since sperm in neat cauda epididymal semen became progressively motile when diluted with neat cauda epididymal plasma as well as accessory sex gland fluid or buffer, composition of the fluid surrounding the sperm is not responsible for the initiation of progressive motility upon dilution nor does cauda epididymal plasma contain an inhibitory factor. Perhaps release from contact immobilization provides the stimulation for the initial acquisition of progressive motility by cauda epididymal sperm. We conclude that during epididymal passage sperm develop from a cell physically unresponsive to changes in cAMP concentration to a form which initiates progressive motility upon changes in cAMP concentration.
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PMID:Adenine nucleotide changes at initiation of bull sperm motility. 17 61

3':5'-Cyclic-AMP phosphodiesterase (PDE) (EC 3.1.4.17) activity was measured in interscapular brown adipose tissue (BAT) and in white epididymal adipose tissue of rats acclimated to constant or fluctuating cold. Experiments were carried out on isolated adipocytes or tissue homogenates. In brown or white adipose tissue or isolated adipocyte homogenates, two different apparent Km values were found according to the substrate (cAMP) concentration. The low Km was at about 10(-6) M and the high one at about 10(-4) M. The apparent V of the high Km enzyme was about 10-fold higher than the V of the low Km enzyme. Cold acclimation to constant or fluctuating cold did not modify appreciably the Km or V values. For low substrate concentrations (10(-6)-10(-8) M), the specific activity of PDE expressed per milligram of protein was decreased in BAT adipocytes of the two groups of cold-acclimated rats, compared to controls. Inversely, it was increased in total tissue homogenates. These variations were smaller in fluctuating cold than in constant cold-acclimate rats. They could, in part, induce the increases in lipolysis and in blood flow observed in the BAT of cold-acclimated rats.
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PMID:3':5'-Cyclic-AMP phosphodiesterase activities in white and brown adipose tissues of cold-acclimated rats. 17 98

The isomers and racemate of trimetoquinol [TMQ; 6-7-dihydroxy-1-(3',4',5'-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline] as well as N-(3',4',5'-trimethoxyphenethyl)dopamine were all shown to be effective at promoting glycerol release from rat epididymal fat tissue. The rank order of potency observed for these compounds was (-)-TMQ greater than or equal to (+/-)-TMQ greater than greater than (+)-TMQ = N-(3',4',5-trimethoxyphenethyl)dopamine. (+/-)-TMQ and (-)-TMQ were the only agents capable of producing a maximal lipolytic response. None of the compounds tested were able to exhibit significant c-AMP phosphodiesterase inhibition. This study is the first report which shows that the beta-adrenoceptor activity of the isomers of TMQ does not correlate with an inhibition of c-AMP phosphodiesterase. An alternate mechanism of action for these compounds is proposed.
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PMID:Phosphodiesterase inhibition and lipolytic action of the stereoisomers of trimetoquinol. 17 6


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