Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The process of insulin release evoked by D-glucose and other nutrient secretagogues is triggered by an increase in cytosolic Ca2+ activity. However, some other insulinotropic agents may stimulate insulin release at a close-to-basal concentration of cytosolic ionized calcium. The control of cytosolic Ca2+ concentration depends not solely on the rate of Ca2+ entry into the cell through voltage-sensitive channels and Ca2+ exit via Na(+)-Ca2+ countertransport or active Ca2+ pumping, but also on the subcellular distribution of Ca2+, as dependent, for instance, on both Ca2(+)-ATPase activity and inositol 1,4,5-triphosphate-sensitive release in microsomes and calcium accumulation in mitochondria. Calmodulin and calbindin were both identified in pancreatic islet cells. Activation of adenylate cyclase by calcium-calmodulin may account for the increased production of cyclic AMP in islets stimulated by nutrient secretagogues. Calbindin is present in both normal and tumoral islet cells, and might participate to the alteration of islet function encountered in vitamin D-deprived or repleted rats. However, no target enzyme for calbindin was yet identified in islet cells. Independently of the role of calcium-binding regulatory proteins, the mitochondrial accumulation of calcium may account in part at least, for the preferential stimulation of mitochondrial oxidative events in the process of nutrient-stimulated insulin release.
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PMID:Calmodulin and calbindin in pancreatic islet cells. 219 50

Previous studies have shown that maturational changes can be induced in a human monocyte line, U937, by treatment with cellfree medium from lectin-stimulated cloned human T lymphocytes or the vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25-[OH]2D3). Many of the maturational effects are accompanied by modification, new synthesis, or reorganization of cell surface membrane constituents, including proteins that function as receptors for ligands that modulate monocyte function. In the present studies, we examined the effects of monocyte differentiation on responsiveness to prostaglandin E2 (PGE)2. We found that the maturational effects of the lymphokine or 1,25[OH]2D3 were accompanied by a marked reduction in the PGE2-induced increase in cellular content of adenosine 3':5'-cyclic monophosphate (cAMP) and a shift in the dose-response curve consistent with a decrease in PGE2 receptor number or binding affinity. Incubation of cells with IFN-alpha or IFN-gamma produced by recombinant DNA technology did not influence PGE2 responsiveness, suggesting that the effects of the lymphokine were not mediated by these products. The absence of an effect on sodium fluoride- or forskolin-induced adenylate cyclase response in membranes prepared from treated cells suggests that the treatment conditions affect PGE2 receptor function rather than the adenylate cyclase enzyme complex. Changes in cell surface receptors for hormones such as PGE2 provide a potential mechanism for modulating the biologic activity of monocyte-macrophages during the process of cellular differentiation.
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PMID:The adenosine 3':5'-cyclic monophosphate response to prostaglandin E2 is altered in U937 cells in association with maturational events induced by activated T lymphocytes and 1,25-dihydroxyvitamin D3. 242 Aug 90

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

Previous work from this laboratory has demonstrated that 25(OH) vitamin D3 [25(OH)D3] acutely suppresses the phosphaturic action of parathyroid hormone (PTH) and interferes with the PTH-induced activation of adenylate cyclase (AC). Calmodulin inhibitors block vitamin D-induced Ca2+ transport in the gut and phosphorus uptake in renal BBMV's. We have examined whether calmodulin antagonists affect the renal action of 25(OH)D3. Acute clearance experiments were performed in PTH-infused parathyroidectomized rats receiving 25(OH)D3 after pretreatment with trifluoperazine (TFP) or promethazine (P). In vitro PTH-induced activation of renal AC was also studied in membrane preparations from pretreated rats in the presence of 25(OH)D3. 25(OH)D3 reduced the PTH-stimulated increase in fractional excretion of phosphorus (CP/CIn) from 0.292 +/- 0.024 to 0.195 +/- 0.018 (p less than 0.005) and urinary cAMP from 149.3 +/- 20.3 to 78.1 +/- 10.4 pmol/min (p less than 0.01) and also blunted AC activation in vitro. TFP but not P abolished the effects of 25(OH)D3 both in vivo and in vitro. R 24571 also abolished the in vitro effect of 25(OH)D3. Thus, (1) TFP abolishes both the antiphosphaturic and the AC/cAMP-related actions of 25(OH)D3, (2) P does not have these effects, and (3) R 24571 abolishes the in vitro effect of 25(OH)D3. These results suggest that the antiphosphaturic effect of 25(OH)D3 acting via the AC/cAMP system may be calmodulin dependent.
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PMID:The in vivo and in vitro effect of calmodulin antagonists on the renal actions of 25(OH) vitamin D3 in the rat. 256 Jan 71

We examined the characteristics of PTH resistance in vitamin D-deficient rats employing renal membranes in vitro. Homologous desensitization was characterized by diminished PTH-stimulated adenylate cyclase activity and was associated with a reduction in PTH-binding capacity, but not affinity. Heterologous desensitization was also seen, as manifested by decreased calcitonin (CT)-stimulated adenylate cyclase activity with normal CT receptor binding. The reduced capacity of the nonhormonal effectors NaF and guanylylimidodiphosphate to stimulate adenylate cyclase indicated a postreceptor defect at the level of the guanyl nucleotide-binding protein (G protein), whereas a normal forskolin response was consistent with a fully functional catalytic component. The G protein deficiency was confirmed by demonstrating that the addition of extracts of vitamin D-sufficient membranes to preparations of vitamin D-deficient membranes restored the normal responses to NaF and guanylylimidodiphosphate. In addition, cholera toxin- and pertussis toxin-catalyzed labeling of vitamin D-deficient renal membranes with [32P]NAD revealed a decrease in both the stimulatory and inhibitory binding proteins. Experiments with testicular membranes in vitro indicated that the adenylate cyclase abnormality was absent in tissue lacking PTH receptors. The results suggest that a major contribution to PTH resistance in vitamin D-deficient animals is a postreceptor defect at the level of the G proteins and that this defect is manifest only in tissue expressing the PTH receptor.
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PMID:Parathyroid hormone desensitization in renal membranes of vitamin D-deficient rats is associated with a postreceptor defect. 283 76

Effects of vitamin D deficiency (-D) on mineral homeostasis were investigated in Japanese quail embryos. The -D embryos from 1,25(OH)2D3-fed hens became progressively calcium deficient, as documented by hypocalcemia and reduced calcium accumulation by the skeleton, yolk sac, and allantoic fluid. Plasma phosphate was progressively elevated between days 11 and 15. Increased calcium accumulation by the skeleton, yolk sac, and allantoic fluid occurred between days 12 and 15 in +D embryos. Phosphate and adenosine 3',5'-cyclic monophosphate (cAMP) concentrations of allantoic fluid increased in +D embryos during the period of shell calcium mobilization. Further increases in phosphate and cAMP excretion into allantoic fluid occurred in -D embryos, although no calcium was absorbed from the shell. Renal 25(OH)D-1-hydroxylase activity increased between days 11 and 13, whereas the adenylate cyclase response to parathyroid hormone was lost in -D embryos by day 14. These changes in renal function are indicative of secondary hyperparathyroidism in the -D embryos. Differentiation of villus cavity and capillary covering cells occurred in the chorionic epithelium of -D embryos, but eggshell calcium was apparently not absorbed. In contrast, 75% of the total body calcium of newly hatched (+D) chicks was obtained from the eggshell. Thus the dissolution and/or transport of eggshell calcium is dependent on vitamin D in quail embryos.
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PMID:Indexes of vitamin D deficiency in Japanese quail embryos. 283 61

We compared the bioactivities of a synthetic truncated NH2-terminal fragment of the human (h) PTH-like peptide (PLP) associated with malignancies [hPLP-(3-34)], an intact NH2-terminal fragment [hPLP-(1-34)], and an NH2-terminal fragment of PTH [hPTH-(1-34)]. Although hPLP-(1-34) was less potent than hPTH-(1-34) in stimulating adenylate cyclase in rat renal membranes, hPLP-(1-34) and hPTH-(1-34) were equipotent in stimulating adenylate cyclase in OK renal cells as well as in UMR 108 osteosarcoma cells in vitro. In osteosarcoma cells, each of these peptides could desensitize adenylate cyclase responses to itself and to the other peptide, but could not reduce stimulation by prostaglandin E2. Renal membranes of vitamin D-deficient rats with secondary hyperparathyroidism had a reduced PLP-stimulated as well as PTH-stimulated adenylate cyclase response. The truncated analog hPLP-(3-34) was only a weak partial agonist and an antagonist in vitro, produced equivalent inhibition of hPLP-(1-34) and hPTH-(1-34) in renal and osseous cells, and could not desensitize agonist responses. In thyroparathyroidectomized rats in vivo, hPLP-(1-34) and hPTH-(1-34) increased cAMP excretion, enhanced phosphaturia, maintained plasma calcium, and reduced calciuria. Equimolar concentrations of hPLP-(3-34) produced no increases above control levels; however, high concentrations of this peptide mimicked PTH actions on renal and plasma ion handling while modestly augmenting cAMP excretion. These results demonstrate the importance of the first two residues of PLP for bioactivity, indicate that PLP and PTH interact at common receptor sites in vivo as well as in vitro, suggest that PLP may not be less potent than PTH in renal target cells, and indicate that the net result of interaction of these peptides with their common receptor in target tissues may reflect both activation and desensitization of receptor-mediated events.
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PMID:Influence of the amino-terminus on in vitro and in vivo biological activity of synthetic parathyroid hormone-like peptides of malignancy. 284 83

The present study was undertaken to investigate the effect of the Hyp mutation and diet-induced hyperparathyroidism on renal responsiveness to PTH and forskolin and to determine whether the renal brush border membrane phosphate transport defect is expressed in the vitamin D- and calcium-deficient Hyp mouse. Our results indicate that PTH is a potent activator of cAMP synthesis in renal slices obtained from vitamin D-replete normal mice and Hyp littermates. However, in the mutants, the amount of cAMP produced in response to similar concentrations of PTH (0.005-5 U/ml) is 55% of normal (P = 0.0076). PTH-dependent cAMP synthesis is significantly reduced in both normal and Hyp mice fed the vitamin D-deficient low calcium diet, and under these conditions, genotype differences are no longer apparent. In contrast, forskolin-stimulated cAMP production is identical in vitamin D-replete normal and mutant mice. Furthermore, cAMP accumulation in response to forskolin is not decreased by diet-induced hyperparathyroidism in either genotype. Vitamin D and calcium deprivation results in a significant decrease in renal brush border membrane Na+-dependent phosphate transport in both genotypes, and under these conditions, the phosphate transport defect persists in Hyp mice. Finally, vitamin D and calcium deprivation has no effect on renal brush border membrane alkaline phosphatase activity. The present results suggest that the catalytic subunit of adenylate cyclase is intact in the mutant strain and that the blunted renal response to PTH in vitamin D-replete Hyp mice as well as in vitamin D- and calcium-deficient mice may be due to uncoupling of the PTH-receptor-adenylate cyclase system. The data also suggest that the expression of the renal phosphate transport defect in Hyp mice is independent of PTH status and alkaline phosphatase activity.
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PMID:Effect of the Hyp mutation and diet-induced hyperparathyroidism on renal parathyroid hormone- and forskolin-stimulated adenosine 3',5'-monophosphate production and brush border membrane phosphate transport. 300 90

The present studies were designed to explore the mechanism underlying skeletal refractoriness to PTH in a vitamin D-deficient animal by assessment of PTH-stimulated cAMP release from isolated perfused bone. In vitamin D-deficient (-D) rats both basal and PTH-stimulated cAMP release were markedly diminished, compared with that in vitamin D-replete (+D) rats. Isolated perfused bones from -D rats that had undergone parathyroidectomy 2 days before death still showed reduced cAMP release in response to PTH, compared with +D bones. To investigate which factors in terms of Ca, endogenous PTH, or vitamin D might primarily be responsible for the impaired PTH-stimulated cAMP release from -D bones, some -D rats were switched to a diet identical to the vitamin D-deficient diet but with high Ca content (4%) for 2 or 5 weeks before death. This schedule maintained normocalcemia despite vitamin D deficiency. PTH-stimulated cAMP release in these rats was increased to a level intermediate between that in -D rats and +D rats, indicating partial restoration of the impaired response to PTH in -D rats. These data indicate that skeletal refractoriness to PTH in vitamin D-deficient animals might, in part, be due to the impaired activation of adenylate cyclase, which cannot be explained entirely by hypocalcemia or associated secondary hyperparathyroidism. Vitamin D deficiency per se, therefore, may play a key role in the impaired cAMP response to PTH.
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PMID:Impaired parathyroid hormone-stimulated adenosine 3',5'-monophosphate release by isolated perfused bones obtained from vitamin D-deficient rats. 300 36

Based on the finding that retinoic acid (RA) increases 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] receptor number in ROS 17/2 cells, we investigated the effects of RA on the ability of 1,25-(OH)2D3 to regulate alkaline phosphatase activity and PTH-responsive adenylate cyclase in these cells. A maximally effective dose of 1,25-(OH)2D3 (10(-8) M) caused a 75-80% increase in alkaline phosphatase activity and an approximately 70-75% attenuation of the cAMP response to PTH, while RA (10(-6) M) decreased alkaline phosphatase activity by 30-45% and decreased PTH-stimulated cAMP levels by approximately 20%. Preincubation with RA did not enhance the 1,25-(OH)2D3-induced increases in alkaline phosphatase activity. The ED50 values for control and RA-treated cultures were approximately 8 X 10(-10) M and 6 X 10(-10) M, respectively. With regard to PTH responsiveness, the effects of RA preincubation on the 1,25-(OH)2D3 attenuation of cAMP response varied with the concentration of 1,25-(OH)2D3. At low doses (less than 10(-9) M), the effects of 1,25-(OH)2D3 and RA were additive. At higher doses of 1,25-(OH)2D3, the effects of RA and 1,25-(OH)2D3 were not additive, and there were no differences between control- and RA-treated cultures. The ED50 values for control- and RA-treated cultures were 10(-10) M and 3 X 10(-11) M, respectively. None of the above effects were observed using equimolar doses of the vitamin D3 metabolites 24,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3. The data show that pretreating ROS 17/2A cells with RA to increase 1,25-(OH)2D3 receptors does not correspond with a concomitant increase in the cellular responsiveness to 1,25-(OH)2D3, as measured by increases in alkaline phosphatase activity and decreases in PTH-responsive adenylate cyclase.
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PMID:Modulation by retinoic acid of 1,25-dihydroxyvitamin D3 effects on alkaline phosphatase activity and parathyroid hormone responsiveness in an osteoblast-like osteosarcoma cell line. 301 60


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