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)

Purified porcine erythrocyte membrane Ca(2+)-ATPase and 3':5'-cyclic nucleotide phosphodiesterase were stimulated in a dose-dependent, saturable manner with the vitamin D-dependent calcium binding protein from rat kidney, calbindin-D28k (CaBP-D28k). The concentration of CaBP-D28k required for half-maximal activation (K0.5 act.) of the Ca(2+)-ATPase was 28 nM compared to 2.2 nM for calmodulin (CaM), with maximal activation equivalent upon addition of either excess CaM or CaBP-D28k. 3':5'-Cyclic nucleotide phosphodiesterase (PDE) also showed equivalent maximum saturable activation by calbindin (K0.5 act. = 90 nM) or calmodulin (K0.5 act. = 1.2 nM). CaBP-D28k was shown to effectively compete with CaM-Sepharose for PDE binding. Immunoprecipitation with CaBP-D28k antiserum completely inhibited calbindin-mediated activation of PDE but had no effect on calmodulin's ability to activate PDE. While the physiological significance of these results remains to be established, they do suggest that CaBP-D28k can activate enzymes and may be a regulator of yet to be identified target enzymes in certain tissues.
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PMID:In vitro enzyme activation with calbindin-D28k, the vitamin D-dependent 28 kDa calcium binding protein. 131 45

The inhibitory effect of prostaglandin E2, histamine, isobutylmethylxanthine, and 1,25-dihydroxyvitamin D3 (1,25-[OH]2D3) on the mitogenic stimulation of peripheral blood lymphocytes from normal and atopic subjects was studied. We found that lymphocytes from atopic patients were less susceptible to inhibition by the three agents that elevate intracellular cyclic adenosine monophosphate (cAMP) concentrations and by the active metabolite of vitamin D (inhibition of 27%, 14%, 12%, and 36% for the atopic patients as compared with 40%, 20%, 22%, and 46% for the normal donors, by the four agents, respectively; p less than 0.02). The inhibitory effect of the cAMP-elevating agents was potentiated by the addition of 1,25-(OH)2D3 to the lymphocyte cultures. The potentiation was more pronounced on lymphocytes from the atopic donors, increasing their responsiveness to levels comparable to levels of lymphocytes from normal donors. The synthetic corticosteroid, dexamethasone, had a similar potentiating effect on the inhibitory action of prostaglandin E2. In view of the beneficial action of beta-agonists, phosphodiesterase inhibitors, and corticosteroids in the treatment of allergy, the potentiating effect of 1,25-(OH)2D3 on the action of cAMP-elevating agents may be of therapeutic interest.
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PMID:1,25-Dihydroxyvitamin D3 potentiates the decreased response of lymphocytes from atopic subjects to agents that increase intracellular cyclic adenosine monophosphate. 170 27

The diterpene forskolin which increases 3',5'-cyclic adenosine monophosphate concentrations (cAMP) in intact cells by directly activating the enzyme adenyl cyclase, was examined for its ability to alter bone resorption in fetal rat long bone cultures. After 48 h, forskolin inhibited resorption at 1.0 and 10 microM. However, after 120 h, it had a small stimulatory effect at 1.0 microM and no net effect on resorption at 10 microM. Isobutyl-methylxanthine (IBMX), which elevates cAMP levels in cells by inhibiting the enzyme 3',5'-cyclic adenosine monophosphate phosphodiesterase, produced a resorptive response which was slightly different from that of forskolin. After both 48 and 120 h, IBMX at 0.1 mM stimulated resorption while at 1.0 mM, it had only inhibitory effects. In bones which were stimulated to resorb with either parathyroid hormone or 1,25(OH)2 vitamin D, forskolin inhibited resorption. The inhibitory effects of forskolin on hormonally stimulated resorption were transient in cultures treated with 1.0 microM but were sustained with 10 microM. Inhibitory responses to forskolin did not appear to result from toxicity since they were completely reversed when forskolin was removed from the media. These results imply that agents which increases 3',5'-cyclic adenosine monophosphate concentrations in bone activate two resorptive pathways: one which is inhibitory and another which is stimulatory.
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PMID:Forskolin has both stimulatory and inhibitory effects on bone resorption in fetal rat long bone cultures. 245 10

Secondary hyperparathyroidism has been attributed to be responsible for the generalized aminoaciduria and phosphaturia of vitamin D deficiency. Since PTH acts in the kidney to generate cAMP, we explored the possibility that its synthetic analog, dbcAMP, would alter the renal transport of taurine (an amino acid lost in the urine in vitamin D deficiency) and Pi. Exposure of renal BBMV prepared from normal and vitamin D-calcium-deficient rats to dbcAMP at concentrations ranging between 10(-4) and 10(-7) M did not alter taurine uptake by these vesicles. Higher dbcAMP concentrations blunted uptake, but these concentrations reduced intravesicular volume, thus representing an artifact of osmolarity. Preincubation of BBMV with dbcAMP for times between 0 and 60 min at 0 or 25 degrees C also did not alter taurine accumulation. Hypotonic lysis of BBMV, allowing entry of the cyclic nucleotide, followed by isotonic resealing did not influence taurine uptake. The addition of potassium fluoride (to inhibit phosphodiesterase activity) and ATP (as an energy source) did not alter taurine accumulation at 60 sec. The uptake of Pi, which is influenced by PTH, was decreased by 25% following exposure to dbcAMP on the internal surface of the vesicle. These data indicate that the taurinuria observed in vitamin D deficiency is unlikely to be related to a PTH-induced increase in intracellular cAMP, unlike the changes in Pi transport, which is sensitive to cyclic nucleotides.
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PMID:Cyclic AMP does not alter taurine accumulation by rat renal brush border membrane vesicles. 255 56

1,25 Dihydroxyvitamin D3 has been shown to stimulate calcium fluxes across skeletal muscle membranes. The involvement of calmodulin in the effects of the metabolite was investigated. Primary cultures of chick embryo skeletal muscle myoblasts and soleus muscles from vitamin D-deficient or 1,25 (OH)2D3-treated chicks were used. Culture of myoblasts and vitamin D-deficient soleus with 1,25 (OH)2D3 (0.05 ng/ml) for 24 and 1 hour, respectively, significantly increased 45Ca uptake by the preparations. In the presence of the calmodulin antagonists flufenazine or compound 48/80 in the uptake medium, no differences between control and treated cultures were observed. The calmodulin content of myoblasts and soleus homogenates and subcellular fractions derived therefrom was estimated by measuring their capacity to stimulate calmodulin-depleted cAMP phosphodiesterase. No changes in total calmodulin cellular content could be detected in response to 1,25(OH)2D3. However, the sterol produced an increase in calmodulin levels of microsomes, mitochondria, and crude myofibrillar fraction and a proportional decrease in cytosolic calmodulin concentration. The 1,25(OH)2D3-dependent changes in calmodulin distribution among subcellular fractions of soleus muscle were observed either in vivo or in vitro. The effects in vitro were already detectable after 5 minutes of treatment with the sterol and parallel 1,25(OH)2D3-dependent changes in tissue Ca uptake. The results suggest that changes in calmodulin intracellular distribution may underly part of the mechanism by which 1,25(OH)2D3 affects muscle calcium transport.
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PMID:1,25 Dihydroxyvitamin D3 affects calmodulin distribution among subcellular fractions of skeletal muscle. 314 26

Studies presented here were designed to investigate further the basis for an impaired cAMP response to parathyroid hormone (PTH) in osteoblastlike calvarial bone cells isolated from vitamin D-deficient rat pups. The goal was to perturb Ca, PTH, and vitamin D in vivo in order to see which factors might be responsible for the impaired in vitro bone cell cAMP response. Pups either were parathyroidectomized (PTX) 3-5 days, implanted with osmotic minipumps delivering high doses of PTH, given repeated, high doses of 1,25(OH)2D3, or were D-deficient (-D, i.e., born and suckled by D-deficient mothers). Osteoblastlike bone cells, isolated by sequential enzyme digestion and centrifugation, were exposed to PTH for 5 min in the presence of a phosphodiesterase inhibitor. In bone cells isolated from -D rat pups, both basal and PTH-induced cAMP accumulation were significantly lower than in +D bone cells. Earlier, we had shown that two daily injections of -D pups with 50 ng 1,25(OH)2D3 restores this reduced bone cAMP response of -D pups toward normal. In the present study, neither basal nor PTH-induced bone cell cAMP accumulation was affected by subjecting D-replete pups to PTX, PTH infusion, or repeated high doses of 1,25(OH)2D3 despite the fact that each treatment markedly changed serum Ca or serum immunoreactive PTH. The results indicate that the impaired bone cell cAMP response seen in -D pups is not a direct result of chronic hypocalcemia and that the "heterologous desensitization" seen in vitro with added 1,25(OH)2D3 could not be duplicated by in vivo treatment of +D pups with supraphysiologic doses of 1,25(OH)2D3.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of vitamin D and parathyroid hormone on cyclic AMP production by bone cells isolated from rat calvariae. 608 11

The influence of vitamin D nutrition on melanogenesis in skin induced by UV radiation was studied in pigmented adult rats. Melanogenesis, assessed by the activity of skin tyrosinase (radiometric assay), was studied in vitamin-D-deficient and vitamin-D-fed rats exposed to UV (0.1 J/cm2, 290-320 nm). The tyrosinase activity in skin was not significantly changed by vitamin D treatment alone. In contrast, the induction of tyrosinase activity provoked by UV radiation was greater in vitamin-D-fed than in vitamin-D-deficient rats. The increase in skin tyrosinase activity in response to UV was preceded by an increase in skin cAMP levels. This rise in cAMP was greater in vitamin-D-treated rats than in vitamin-D-deficient rats. The pretreatment of rats with phosphodiesterase inhibitor potentiated the effect of vitamin D on skin tyrosinase activity. The low serum calcium levels in the vitamin-D-deficient group were evidently not responsible for the lower UV induction of skin tyrosinase activity because the vitamin-D-deficient rats with normal serum calcium levels (supplemented with 20% lactose and 2% calcium in the diet) were also unable to show maximal induction of skin tyrosinase activity in response to UV radiation requires the presence of adequate vitamin D. cAMP may be involved in the mediation of this effect. The relationship observed between the vitamin D status of animals and tyrosinase activity of skin could provide an effective feed-back control for protection against UV and vitamin D intoxication.
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PMID:Vitamin D nutrition increases skin tyrosinase response to exposure to ultraviolet radiation. 617 46

We used an in vivo infusion technique to assess the hypothesis that vitamin D metabolites and estrogens modulate tissue responsiveness to parathyroid hormone via effects on the adenylate cyclase-cAMP system. After treatment with these agents for 3-4 days, rats were thyroparathyroidectomized. Twenty-four hours later, parathyroid extract (PTE) was infused, and cAMP in calvaria was measured. The response to PTE was achieved by 2 min and represented a 4-fold increase in the tissue concentration of cAMP at the highest dose of hormone tested. Treatment with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], did not affect cAMP levels in bone. However, 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3], either 0.25 or 1.25 micrograms daily, led to a major increase in PTE-stimulated cAMP formation, a result which persisted when carried out in chronically thyroparathyroidectomized animals. This effect did not reflect direct stimulation of adenylate cyclase or inhibition of cyclic nucleotide phosphodiesterase from bone by the vitamin metabolite, nor did it operate via the 1,25-(OH)2D3 receptor. 24,25-(OH)2D3 treatment also increased cAMP concentrations in renal cortical slices, but not in liver. Adenylate cyclase activity in kidneys from 24,25-(OH)2D3-treated rats was not different from that found in control tissue, but total cytosol phosphodiesterase activity was diminished. 17 beta-Estradiol, over a daily dose range of 2.5 micrograms to 5.0 mg, lowered basal cAMP levels but did not alter PTE-stimulated cAMP production. We conclude that modulation of PTH action in bone by estrogen does not involve modification of the acute cAMP response to PTH. Further, the results support the concept that there are unique actions of 24,25-(OH)2D3 on bone and kidney which are not duplicated by 1,25(OH)2D3.
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PMID:Effects in vivo of vitamin D metabolites and 17 beta-estradiol on parathyroid hormone-dependent formation of adenosine 3',5'-monophosphate in rat bone. 625 69

The adenylate cyclase activation by bovine synthetic parathyroid hormone (bPTH) (1-34) was studied in vitro in kidney plasma membranes from D-deficient (D-Mb) or normal (D+Mb) rats. In D-Mb, the apparent affinity of parathyroid hormone (PTH) for membranes (170 +/- 30 nM) was significantly higher than that measured in D+Mb (55 +/- 5 nM). The maximum velocity of the PTH-stimulated adenylate cyclase was significantly higher in D+Mb than in D-Mb (163.0 +/- 13.7 and 93.4 +/- 6.7 pmol of cAMP/mg of protein/min, respectively). The action of vitamin D metabolites on the adenylate cyclase stimulation by PTH was then studied in vitro in D-Mb and D+Mb. In D-Mb, 25-hydroxyvitamin D3, 24,25-, and 1, 25-dihydroxyvitamin D3 significantly inhibited cAMP production in the presence of 0.87 microM of bPTH. Vitamin D3 had no effect. Maximal inhibition (86%) was observed for 1,25-dihydroxyvitamin D3. 1,25-Dihydroxyvitamin D3 decreased the maximum velocity of PTH-stimulated adenylate cyclase but did not modify the bPTH apparent affinity for D-Mb. The vitamin D3 metabolites tested did not modify the cyclase stimulation by isoproterenol, sodium fluoride, or 5'-guanylylimidodiphosphate. The presence of 1,25-dihydroxyvitamin D3 or 25-hydroxyvitamin D3 did not increase the (Na-K)-ATPase or the phosphodiesterase activities. In the presence of 1,25-dihydroxyvitamin D3 and bPTH, the apparent affinity of ATP for the catalytic moiety was not modified. The maximum velocity was decreased. These results suggest an in vitro interaction between hydroxylated vitamin D metabolites and kidney membranes PTH receptor.
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PMID:Renal parathyroid hormone-dependent adenylate cyclase in vitamin D-deficient rats. Inhibition by hydroxylated vitamin D3 metabolites. 625 64

In contrast to dibutyryl cyclic AMP, the methylxanthine phosphodiesterase inhibitors theophylline and caffeine were found to inhibit the conversion of 25 hydroxyvitamin D3 to 1,25 dihydroxyvitamin D3 in isolated renal tubules from vitamin D deficient chicks. This inhibition occurred at concentrations of methylxanthines which were shown to increase renal tubule cyclic AMP levels. No effect of theophylline or caffeine on 25 hydroxyvitamin D3 metabolism in isolated chick renal mitochondria was detected. Because of a demonstrated inhibitory action of calcium (10 and 20 mumol/l) on renal mitochondrial conversion of 25 hydroxyvitamin D3 to 1,25 dihydroxyvitamin D3, the effect of theophylline and dibutyryl cyclic AMP on cellular calcium-45 efflux and total renal tubule calcium content was estimated. Theophylline 10 mmol/l was found to inhibit renal tubular calcium efflux and to increase total cellular calcium content, while dibutyryl cyclic AMP 1 mmol/l had the reverse effect on both parameters. Divergent actions of the methylxanthines and dibutyryl cyclic AMP on the formation of 1,25 dihydroxyvitamin D3 and renal tubule calcium efflux and content support the hypothesis that intracellular calcium is an important regulator of renal vitamin D metabolism. The results indicate that observed actions of methylxanthines cannot always be ascribed to cyclic AMP accumulation.
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PMID:Opposing actions of methylxanthines and dibutyryl cyclic AMP on 1,25 dihydroxyvitamin D3 production and calcium fluxes in isolated chick renal tubules. 632 99


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