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 recently discovered heat-stable inhibitor protein of the Ca2+-activated cyclic nucleotide phosphodiesterase (Sharma, R. K., Wirch, E. & Warg, J. H. (1978) J. Biol. Chem., in press) has been purified 238 214-fold from bovine brain extract using an affinity column of the modulator protein--Sepharose 4B conjugate. The purified sample appears to be homogeneous as judged by sodium dodecyl sulphate (SDS) gel electrophoresis. The protein band has a mobility corresponding to that of a polypeptide of molecular weight 68 000. Since the heat-stable inhibitor protein has a molecular weight of 70 000 under nondenaturing conditions, it suggests that it is a monomeric protein. The protein has no inhibitory activity toward the cAMP-dependent protein kinase or protein phosphatase. The purified sample has been tested for various enzyme activities which include ATPase, GTPase, cAMP phosphodiesterase, cGMP phosphodiesterase, 5'-nucleotidase, and protein kinase. None of these activities are exhibited by the purified sample.
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PMID:Purification of the heat-stable inhibitor protein of the Ca2+-activated cyclic nucleotide phosphodiesterase by affinity chromatography. 20 31

The ability of isoproterenol, glucagon, PGE1 and cholera toxin to stimulate the synthesis of cAMP and protein kinase activity in line of liver cells (BRL) and a line of rat hepatoma cells (H35) has been determined. The concentration of cAMP in BRL cells (approximately 10 pmoles/mg protein) is in the range reported for other cultured cell lines but H35 cells contain extraordinarily low amounts of this cyclic nucleotide (approximately 0.05 pmoles/mg protein). Isoproterenol and PGE1 caused an increase in cAMP content, and protein kinase activation in BRL cells, although glucagon was ineffective. H35 cells, in contrast, were completely insensitive to all hormonal agonists. Despite this fact, cholera toxin was able to produce a marked increase in cAMP content, adenylate cyclase activity and protein kinase activation in H35 cells. binding studies with [125 I]-iodohydroxybenzylpindolol, a specific beta-adrenergic receptor antagonist, revealed that each H35 cell possesses fewer than 10 beta-adrenergic receptors whereas BRL cells contain 2-5,000 receptors per cell. The low level of cAMP in H35 cells appears to result from a combination of totally unstimulated adenylate cyclase and apparently elevated phosphodiesterase activities.
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PMID:Studies of cAMP metabolism in cultured hepatoma cells: presence of functional adenylate cyclase despite low cAMP content and lack of hormonal responsiveness. 20 52

The enzyme activities of cyclic AMP system in the neuro- and adenohypophyses were studied, immediately after an irradiation by a single whole body exposure of 1600 R, in an attempt to find whether this intervention causes the changes in the responsiveness of the cyclic AMP regulatory system. In the irradiated rats the neurohypophyses revealed a reduced activity of adenylate cyclase, moderately increased activity of phosphodiesterase and slightly decreased activity of protein kinase, including the value stimulated by cyclic AMP. In the adenohypophyses the irradiation did not cause any significant changes in the enzyme activities of the cyclic AMP system, except of slightly decreased adenylate cyclase activity. The possible relationship of the plasma level of antidiuretic hormone immediately after irradiation and the enzyme activities of cyclic AMP system is discussed.
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PMID:Effect of irradiation on enzyme activities of cyclic AMP system in the neuro- and adenohypophyses. 21 Apr 9

In previous studies, cystic fibrosis (CF) fibroblasts were demonstrated to be resistant to the cytotoxic effects of ouabain, dexamethasone, and the sex hormones, dihydrotestosterone, 17beta-estradiol, and progesterone. We now show that CF fibroblasts also exhibit greatly increased resistance to the cytotoxic effects of exogenous dibutyryl cyclic AMP (cAMP), as well as to isoproterenol and theophylline, drugs which are known to increase endogenous levels of cAMP. CF cells were also shown to have normal amounts of (3H)cAMP binding to protein kinase as well as normal amounts of cAMP-stimulated protein kinase activity. Phosphodiesterase in CF cells was also found to be stimulated by cAMP to the same degree as in normal cells. These findings suggest that there is no detectable protein kinase deficiency in CF cells. cf cells thus appear to be unlike some cAMP-resistant mutants described by others which are defective in protein kinase activity and cAMP regulation of phosphodiesterase levels. The cross-resistance of CF fibroblasts to ouabain, steroid hormones, and cAMP may provide a unique opportunity to study the biochemical events involved in the metabolism of these drugs as well as the basic biochemical defect in a common human genetic disease.
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PMID:Pleiotropic drug resistance in cystic fibrosis fibroblasts: increased resistance to cyclic AMP. 21 May 26

Regulation of cyclic AMP-dependent protein kinase, cyclic AMP-receptor activity and intracellular cyclic AMP concentrations by choriogonadotropin was studied in ovarian cells prepared from 26-day-old rats. A close correlation was observed between phospho-transferase activity and cyclic AMP-receptor activity in 12000g supernatant fractions from rat ovarian homogenate. The apparent activation constant (K(a)) and I(50) (concentration required to produce 50% inhibition) of different cyclic nucleotides for phosphotransferase and cyclic AMP receptor activities respectively were also determined. Cyclic AMP and 8-bromo cyclic AMP were most effective, giving K(a) values of 0.08 and 0.09mum and I(50) of 0.12 and 0.16mum respectively. Other nucleotides were also effective, but required higher concentrations to give a comparable effect. An increased concentration of cyclic AMP produced by choriogonadotropin (1mug/ml) treatment was accompanied by decreased cyclic AMP binding as early as 5min after hormone addition. Choriogonadotropin also stimulated the protein kinase activity ratio (-cyclic AMP/+cyclic AMP) under identical experimental conditions. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine potentiated the action of choriogonadotropin on the three parameters measured in a dose- and time-dependent manner. The maximal cyclic AMP-binding capacity, as determined by cyclic AMP-exchange assay, remained unchanged before and after hormone addition. The endogenously bound cyclic AMP was determined from the difference between the maximal binding capacity and the exogenously bound cyclic AMP. With different choriogonadotropin concentrations, a quantitative correlation was established between maximal binding capacity, exogenous binding and endogenous binding activities. Approx. 60% of total binding sites were endogenously occupied in untreated cells, and choriogonadotropin (1mug/ml) treatment fully saturated available binding sites with a parallel 10-fold increase in cellular cyclic AMP. The present results provide evidence for a probable intracellular compartmentalization of cyclic AMP in the ovarian cell, and suggest that in the unstimulated state all cyclic AMP present in the ovarian cell may not be available for protein kinase activation.
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PMID:Adenosine 3':5'-cyclic monophosphate-dependent protein kinase(s) of rat ovarian cells. Gonadotropin regulation of adenosine 3':5'-cyclic monophosphate-receptor activity. 21 Jul 60

Initial and transient increases in the basal levels of cyclic GMP in the heart were noted prior to cardiac hypertrophy in rats administered isoproterenol. Increased levels of cyclic AMP-phosphodiesterase (in both the soluble and particulate fractions) and stimulatory modulator of cyclic GMP-dependent protein kinase, however, were associated with the progression, or the state, of cardiomegaly, with their levels returning to the control values upon regression of the hypertrophy. The levels of cyclic GMP phosphodiesterase in the soluble fraction were lower, whereas those in the particulate fraction were higher, in the hypertrophied heart than the control. In cardiac hypertrophy, the maximal activity ratio(--cyclic AMP/+cyclic AMP) of cyclic AMP-dependent protein kinase in the incubated minced heart caused by isoproterenol was lower, whereas the concentration of isoproterenol required to increase the activity ratio half-maximally was higher than controls; the reduced responsiveness to the drug, however, was reversed when the hypertrophy regressed. These observations, taken collectively, appear to suggest that the desensitization of the beta-adrenergic mechanism seen in the cardiac hypertrophy produced by repeated administration of isoproterenol is associated with adaptive modifications in certain parameters of the cyclic nucleotide systems.
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PMID:Alterations in activities of cyclic nucleotide systems and in beta-adrenergic receptor-mediated activation of cyclic AMP-dependent protein kinase during progression and regression of isoproterenol-induced cardiac hypertrophy. 21 Aug 40

Long-term (48-hr) incubations of either the fibroblast strain WI-38 or its SV40-transformed counterpart, WI-38-VA13-2RA, in growth medium containing 1 micron prostaglandin E1 (PGE1) resulted in a sustained production and release of cyclic AMP from the cells into the medium. Despite the steady production, intracellular levels of the nucleotide decreased, reaching steady-state values within 4 hr of the initial exposure to PGE1. These values were maintained for the remainder of the 48-hr experimental period. The steady-state levels of intracellular cyclic AMP were higher than those observed in unstimulated cells, and cyclic AMP-dependent protein phosphokinase was in a highly activated state as compared to controls. Under these conditions little change in the growth or morphology of either the normal or transformed cells was observed. In contrast, inhibition of growth, apparent cell death, and unusual morphological changes were observed in both normal and transformed cells when high concentrations of either PGE1 (10 micron) or the phosphodiesterase inhibitor 1-methyl, 3-isobutylxanthine (0.5 mM to 2 mM) were used, which was indicative of toxic effects of the drugs. It was concluded that cyclic AMP-mediated activation of protein phosphokinase does not completely inhibit growth in WI-38 cells or restore normal growth and morphology to the SV40-transformed cells.
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PMID:Prolonged prostaglandin E1 stimulation of cyclic AMP production in transformed and normal WI-38 fibroblasts. 21 38

The effects of noradrenaline (NA) and isopropyl-noradrenaline (ISNA) on glycerol release and cAMP levels in sc adipose tissue were studied in vitro in 27 patients with hyperthyroidism. In 11 patients, the studies were repeated after 6--12 months of treatment for hyperthyroidism. A third group comprised 21 euthyroid patients otherwise healthy except for morbid obesity. The lipolytic response to ISNA, observed in untreated thyrotoxic patients, was found to be reduced by 30% when the patients were reexamined after treatment for thyrotoxicosis. This reduction was attributable to a decrease in the cAMP level. This was observed whether adipose tissue was incubated in the presence or absence of a phosphodiesterase inhibitor, theophylline. Both NA and ISNA induced 50% more rapid glycerol release and 4 times higher cAMP levels in adipose tissue of the thyrotoxic subjects than in the obese euthyroid patients. A positive correlation between tissue cAMP and glycerol release, on one hand, and mean fat cell size, on the other hand, was observed in treated thyrotoxic patients and obese euthyroid patients but was not recorded in the untreated hyperthyroid patients. The basal rate of lipolysis was not altered in thyrotoxicosis. The results suggest that the enhanced lipolytic response to catecholamines in adipose tissue of hyperthyroid patients is due to increased beta-adrenergic responsiveness. In addition, a disruption in subsequent stages of the regulatory pathway at the level of protein kinase or hormone-sensitive lipase also seems possible.
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PMID:Regulation of lipolysis by human adipose tissue in hyperthyroidism. 21 92

Parathyroid hormone (PTH) and glucagon increase the urinary fractional excretion of phosphate, but insulin administration is associated with a decreased fractional excretion of phosphate. It was the purpose of this study to determine whether insulin will antagonize the effects of PTH and glucagon on cAMP levels and protein kinase activation of rat renal cortex. In situ incubation studies were performed on rat renal cortical slices exposed to insulin, PTH, and glucagon. Insulin alone did not affect the tissue cAMP and cGMP levels or the state of protein kinase activation. Preincubation of slices with insulin, however, did significantly inhibit increases in protein kinase activation induced by both PTH and glucagon. Insulin also significantly inhibited PTH-stimulated increases in tissue cAMP levels, but did not blunt the elevations of cAMP levels induced by glucagon. Insulin (10(-9) M) had no effect on either the in vitro activity of adenylate cyclase, basal or PTH-stimulated, or on the activities of low Km cytosolic or membrane-bound cAMP phosphodiesterase. The data show that insulin antagonizes activation of protein kinase by both PTH and glucagon in renal cortex. Separate mechanisms are probably involved for PTH and glucagon interaction. The antiphosphaturic effect of insulin in vivo may result in part from this antagonism at the cellular level.
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PMID:Insulin inhibition of hormone-stimulated protein kinase systems of rat renal cortex. 22 Aug 84

A series of 2'-O-acyl derivatives of 6-thioinosine cyclic 3',5'-phosphate (6-HS-cRMP) were prepared and examined for their cytotoxic effects on S49 mouse lymphoma cells which were deficient in hypoxanthine-guanine phosphoribosyltransferase (HGPRTase). Cytotoxicity increased with the lipophilicity of the acyl group to a lowest EC50 of 65 micrometer for the 2'-O-palmityl derivative. Addition of a mutation in the gene for cAMP-dependent protein kinase to the HGPRTase-deficient cell line confers resistance to 2'-O-butyryl-cAMP but not to 2'-O-butyryl-6-HS-cRMP, indicating that the latter does not exert its toxic effect via activation of protein kinase. The time course of cell kill by 2'-O-palmityl-6-HS-cRMP resembled that of 6-mercaptopurine and not that of cyclic AMP in these cells. The data suggest that the intact cyclic nucleotides are penetrating the cells and being converted, by phosphodiesterase action and deacylation, to the first toxic metabolite of 6-mercaptopurine, thioinosinic acid.
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PMID:2'-O-Acyl-6-thioinosine cyclic 3',5'-phosphates as prodrugs of thioinosinic acid. 22 58


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