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 effect of different doses of luteinizing hormone on activation of protein kinases, cyclic AMP and testosterone production was studied in purified rat testis Leydig-cell preparations in the presence of 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor). In addition, the nature of the protein kinases present in these cells and other tissues was investigated. The following results were obtained. 1. With all the amounts of luteinizing hormone used (0.1-1000 ng/ml), both activation of protein kinase and stimulation of testosterone production were demonstrated. With the lowest amount of luteinizing hormone (0.1 ng/ml), an 8.4+/-0.9% (S.E.M.,n=6) stimulation of protein kinase activation occurred, increasing to 100% with 1000 ng/ml, compared with 3.2+/-1.0%(S.E.M.,n=7) and 100% stimulation of testosterone production with 0.1 and 100 ng/ml respectively. 2. With amounts of luteinizing hormone up to 1 ng/ml (which gave half-maximal stimulation of testosterone production) no detectable increases in net cyclic AMP production were obtained. With higher amounts of luteinizing hormone, cyclic AMP production increased, but maximal production was not reached with 1000 ng/ml. 3. Two isoenzymic forms of protein kinase were present in Leydig cells and seminiferous tubules; type I was eluted with 0.075 M-and type II with 0.22-0.25 m-NaCl from DEAE-cellulose columns. 4. The protein kinase activity was not affected by the presence of erythrocytes in the Leydig-cell preparation, but varied depending on the type of histone used as substrate (histone F2b greater than mixed greater than histone F1).
Biochem J 1976 Dec 15
PMID:Correlation of protein kinase activation and testosterone production after stimulation of Leydig cells with luteinizing hormone. 18 52

A homogeneous preparation of venom phosphodiesterase from Crotalus adamanteus possesses an intrinsic endonuclease activity, specific for superhelical (form I) and single-stranded DNA. The phosphodiesterase degrades single-stranded T7 DNA by endonucleolytic cleavages. Duplex T7 DNA is hydrolyzed by the liberation of acid-soluble products simultaneously from the 3' and 5' termini but without demonstrable internal scissions in duplex regions. Since venom phosphodiesterase is known to hydrolyze oligonucleotides stepwise from the 3' termini, the cleavage at the 5' end of duplex T7 DNA is ascribed to an endonuclease activity. Form I PM2 DNA is nicked to yield first relaxed circles and then linear DNA which is subsequently hydrolyzed only from the chain termini. The linear duplex DNA intermediates consist of a discrete series of fragments (11 are usually resolved on agarose gels) with initial molecular weights ranging from 6.3 x 10(6) (the intact PM2 DNA size) to approximately 1 x 10(6). The cleavage of the form I molecule must, therefore, occur at a limited number of unique sites. The enzyme also cleaves nonsuperhelical, covalently closed circular PM2 DNA but at a 10(4) times slower rate. Both the endonuclease activity on form I DNA and the known exonuclease activity co-migrate on polyacrtkanude gels, are optimally active at pH 9, are stimulated by small concentrations of Mg2+, and are similarly inactivated by heat, reducing agents, and EDTA.
J Biol Chem 1977 Dec 10
PMID:An endonuclease activity of venom phosphodiesterase specific for single-stranded and superhelical DNA. 20 Jun 16

3':5'-Cyclic-AMP phosphodiesterase (EC 3.1.4.17) and the activating factor of cyclic nucleotide phosphodiesterase were detected in cultured human cell lines from patients with lymphoblastic leukemia and retinoblastoma and in the Brown-Pearce (rabbit) carcinoma. The homogenate of lymphoblasts contained levels of the activating factor in excess of that required to produce maximal activation of the endogenous phosphodiesterase. The activating factor found in these malignant cells appears to be similar to the calcium-binding protein activator of bovine brain phosphodiesterase on the basis of the molecular weight obtained from gel filtration, electrophoretic patterns, calcium requirement for the activity, and the effect of calcium on the proteolysis. In addition, the tumor-derived activator was able to restore the activity of activator-deficient phosphodiesterase from the bovine brain.
J Natl Cancer Inst 1977 Dec
PMID:Cyclic nucleotide phosphodiesterase and protein activator in human cancer cell lines and Brown-Pearce carcinoma. 20 Jul 56

Papaverine enhances the spontaneous release of 3H-dopamine from rat brain striatal synaptosomes and 3H-noradrenaline from cortical synaptosomes in a dose-dependent way. Neither dibutyryl cyclic AMP nor theophylline had any significant effect on either spontaneous or on potassium-evoked 3H-catecholamine release. It is suggested that the effect of papaverine on catecholamine release is not due to its phosphodiesterase inhibitory potency.
Eur J Pharmacol 1977 Dec 15
PMID:The effects of dibutyryl cyclic AMP, theophylline and papaverine on the release of 3H-catecholamines from rat brain striatal and cortical synaptosomes. 20 72

Substances known to alter cyclic nucleotide levels in cells were applied to the isolated toad retina and effects on rod electrical and adaptive behavior were studied. The retina was continually superfused in control ringer's or ringer's containing one or a combination of drugs, and rod activity was recorded intracellularly. Superfusion with cGMP, Bu(2)GMP, isobutylmethylxanthine (IBMX; a phosphodiesterase inhibitor), or PGF(2alpha) (a prostaglandin) caused effects in rods that closely match those observed when extracellular Ca(2+) levels were lowered. For example, short exposures (up to 6 min) of the retina to these substances caused depolarization of the membrane potential, increase in response amplitudes, and some changes in waveform; but under dark-adapted or partially light-adapted conditions receptor sensitivity was virtually unaffected. That is, the position of the V-log I curve on the intensity axis was determined by the prevailing light level, not by drug level. These drugs, like lowered extracellular Ca(2+), also decreased the period of receptor saturation after a bright-adapting flash, resulting in an acceleration of the onset of membrane and sensitivity recovery during dark adaptation. Long-term (6-15 min) exposure of a dark-adapted retina to 5 mM IBMX or a combination of IBMX and cGMP caused a loss of response amplitude and a desensitization of the rods that was similar to that observed in rods after a long-term low Ca(2+) (10(-9)M) treatment. Application of high (3.2 mM) Ca(2+) to the retina blocked the effects of applied Bu(2)cGMP. PGE(1) superfusion mimicked the effects of increasing extracellular Ca(2+). The results show that increased cGMP and lowered Ca(2+) produce similar alterations in the electrical activity of rods. These findings suggest that Ca(2+) and cGMP are interrelated messengers. We speculate that low Ca(2+) may lead to increased intracellular cGMP, and/or that applied cGMP, and/or that applied cGMP may lower cytosol Ca(2+), perhaps by stimulating Ca(2+)- ATPase pumps in the outer segment.
J Gen Physiol 1977 Dec
PMID:Electrical and adaptive properties of rod photoreceptors in Bufo marinus. II. Effects of cyclic nucleotides and prostaglandins. 20 24

Endotoxin lipopolysaccharide (LPS) from Acinetobacter 199A induced aggregation of blood platelets from immune adherence-positive species (rat, rabbit) but not from immune adherence-negative species such as pig and man. Aggregation occurred in 2 phases: the first was not accompanied by secretion of platelet constituents, was apparently a consequence of C3 activation, and was selectively inhibited by EGTA. The second phase of aggregation was associated with secretion of platelet granule contents, and with a lesser amount of cytoplasmic leakage. Secondary aggregation was abolished by the sulphydryl alkylating agent N-ethylmaleimide, and by agents which increased the level of cyclic AMP in platelets, such as prostaglandin E1 (a stimulator of adenylate cyclase) and methyl xanthines (inhibitors of phosphodiesterase). Secondary aggregation was partly inhibited by agents which block platelet prostaglandin biosynthesis (e.g. aspirin, indomethacin). Primary aggregation was unaffected by these inhibitors at concentrations which blocked secondary aggregation.
J Cell Sci 1977 Dec
PMID:Endotoxin-induced platelet aggregation and secretion. I. Morphological changes and pharmacological effects. 20 8

Rats were injected daily with 1.3 mumol/kg of haloperidol s.c. for 10 days. From the second to the ninth day after haloperidol withdrawal the rats developed supersensitivity to the behavioral affects of apomorphine. Concomitantly, the Ka of dopamine for the activation of striatal adenylate cyclase was lowered and the striatal content of the Ca2+ dependent protein that activates cAMP phosphodiesterase was increased. This activator protein is stored in striatal membranes and can be released by membrane phosphorylation in cytosol. This protein increases the activity of the high Km phosphodiesterase (Uzunov et al., 1976) but when it is bound to striatal membranes it facilitates the activation of striatal adenylate cyclase by dopamine (Gnegy et al., 1976b). The increase in protein activator content of striatal membranes caused by haloperidol could be a primary factor in causing supersensitivity to the biochemical and behavioral effects of dopamine receptor agonists.
Naunyn Schmiedebergs Arch Pharmacol 1977 Dec
PMID:Correlation between drug-induced supersensitivity of dopamine dependent striatal mechanisms and the increase in striatal content of the Ca2+ regulated protein activator of cAMP phosphodiesterase. 20 83

11 patients with histories of clinical bleeding were selected as examples of platelet release abnormality. Mean bleeding time was 18 +/- 2.6 min (normal +/- SEM; 6 +/- 0.44); mean platelet adhesiveness was 9.9 +/- 4.3% (normal +/- SEM; 30 +/- 2.2). Clot retraction and platelet factor 3 were normal. Platelet aggregation with adenosine diphosphate (ADP), epinephrine and collagen was decreased, as was 14C-serotonin release. Electron microscopic studies of platelets exposed to epinephrine showed 2 subgroups: one which failed to aggregate or have centralization of organelles and a second which developed pseudopodia and centralization of organelles, but rarely aggregated or degranulated. Measurements of activity of adenylate cyclase and phosphodiesterase under basal conditions were performed on platelets from patients and control subjects. Adenylate cyclase activity was significantly lower and phosphodiesterase activity significantly higher in the patient group. Prostaglandin E1 was a potent stimulator of adenylate cyclase in both groups, as was NaF. It was concluded that the causative defects with "platelt release abnormality" do not reside in either the activity of adenylate cyclase or of phosphodiesterase. Changes in formation and destruction of cyclic adenosinemonophosphate (AMP) may instead be regarded as a compensatory response to a defect in another effector system.
Thromb Haemost 1977 Dec 15
PMID:Adenylate cyclase and phosphodiesterase activity in the platelet release abnormality. 20 56

A calcium-dependent cyclic nucleotide phosphodiesterase from rat cerebrum was, in the absence of activator protein, inhibited by various monovalent cations. The inhibition was rapid, readily reversible, and concentration-dependent, with 100 mM cesium, rubidium, or potassium ion inhibiting essentially all basal enzyme activity, while 100 mM sodium or lithium ions produced only moderate inhibition. The potency of the cations in inhibiting the enzyme was Cs greater than or equal to Rb greater than K greater than Na greater than or equal to Li. Potassium ions increased the apparent Km for cyclic GMP and cyclic AMP by 3- and 5-fold, respectively. At 100 mM, the monovalent cations inhibited enzyme activated by the calcium-dependent activator by only 15 to 30%, while at 55 mM no inhibition pertained. Potassium and sodium ions at 55 mM had no effect on the calcium-independent phosphodiesterase from rat cerebrum. The results indicate that at normal intracellular concentrations of potassium ions the activity of the calcium-dependent phosphodiesterase is virtually completely dependent on the presence of calcium plus activator protein.
J Biol Chem 1978 Dec 25
PMID:Calcium-dependent 3':5'-cyclic nucleotide phosphodiesterase. Inhibition of basal activity at physiological levels of potassium ions. 21 28

Treatment of rat ventricular cells with 10 mM EGTA makes the sarcolemma highly permeable to small ions and molecules without removing its restriction of the diffusion of larger molecules or inactivating all of its enzymatic functions. These hyperpermeable cardiac cells have been used to study the regulation of the range of concentration of Ca over which activation of the contractile proteins occurs (Ca sensitivity). The Ca sensitivity can varied from three- to sixfold without any significant alteration in the general shape of the relation between force and Ca concentrations. Although cyclic nucleotides in concentrations of 10(-9) to 10(-5) M do not influence Ca sensitivity, in the presence of a phosphodiesterase inhibitor, cGMP increases and cAMP decreases Ca sensitivity. Treatment of the hyperpermeable cells with a nonionic detergent raises Ca sensitivity as does removal of the phosphate donor by complete substitution of CTP for ATP. These data indicate that Ca sensitivity is probably modulated by a cAMP-dependent phosphorylation that decreases Ca sensitivity. The sarcolemma is required for this reaction to take place. The effect of this reaction is antagonized by a cGMP-dependent reaction occurring inside the cell. Studies involving the perfusion of the heart with and without epinephrine before the exposure to EGTA indicate that epinephrine can regulate this system of control of Ca sensitivity. The functional considerations of this regulatory system are discussed.
J Gen Physiol 1978 Dec
PMID:The regulation of the calcium sensitivity of the contractile system in mammalian cardiac muscle. 21 1


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