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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Direct application of parathyroid hormone (PTH) to renal proximal tubule in vitro stimulates the adenylate cyclase system which in turn causes reduction in phosphate (P) reabsorption. Similar application of parathyroid extract to rat jejunum fails to induce changes in P transport. In the present study we examined the basis for this PTH-unresponsiveness in rat jejunum. The effect of PTH, and another peptide hormone, salmon calcitonin (SCT) and sodium fluoride (NaF) on jejunal adenylate cyclase activity was first examined in both vitamin D-deficient (-D) rats and similar rats after 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] repletion. Jejunal cyclic 3',5'-AMP (cAMP, pmol/mg protein/min) increased from 11.0 +/- 1.1 in -D rats to 23.0 +/- 2.2 in 1,25(OH)2D3-repleted rats (p less than 0.001). Neither PTH nor SCT had any effect on adenylate cyclase activity in jejunum from either -D or 1,25(OH)2D3-repleted rats. NaF caused the anticipated stimulation in cAMP generation, a response independent of the vitamin D nutritional status of the animal [-D: 76.8 +/- 1,25(OH)2D3: 86.9 +/- 8.5]. We then examined the question if exogenous cAMP, which reduces renal P reabsorption, also causes decrease in intestinal P absorption. The effect of dibutyryl cAMP (DbcAMP) on transepithelial, net P absorption was examined in short-circuited jejunal epithelia from rats maximally stimulated by 1,25(OH)2D3. DbcAMP caused the anticipated increase in short-circuit current (+212%) without affecting the net, active P absorption. We conclude that, unlike the renal proximal tubule, the adenylate cyclase system in jejunum is insensitive to PTH, and the P absorptive mechanism is resistant to cAMP.
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PMID:Jejunal phosphate transport is not regulated by the PTH-adenylate cyclase system. Further studies on the contrasting features between intestinal and renal phosphate transport mechanisms. 302 18

In short-term experiments, male Wistar rats were made diabetic for 10 days with a single injection of streptozotocin (65 mg/kg body weight). One group of diabetic rats was treated with insulin for 3 days prior to sacrifice. In long-term experiments, vitamin D replete or vitamin D depleted rats were made diabetic for 6 weeks. Criteria for diabetes were loss of weight, glycosuria (Tes-Tape), and hyperglycemia. In long-term diabetic rats the activity of renal mitochondrial 25-hydroxyvitamin D3 (25-(OH)D3) 1 alpha-hydroxylase was significantly decreased and that of 25-(OH)D3 24-hydroxylase increased. However, the parathyroid hormone (PTH) sensitive renal adenylate cyclase activity of diabetic rats was not different from that of the nondiabetic rats in either the vitamin D replete group or the vitamin D depleted group. On the other hand, the PTH-sensitive renal adenylate cyclase activity was significantly higher in short-term diabetic rats than in control and insulin-treated rats. These differences were observed at doses of 10(-8) to 10(-5) M of PTH. This study has demonstrated for the first time that there are differences in the PTH-sensitive adenylate cyclase response between long-term and short-term diabetic rats. The hypersensitivity to PTH of the renal adenylate cyclase observed in short-term diabetic rats probably represents a response to insulin deficiency during the early development of diabetes mellitus in the rats.
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PMID:Effect of long-term and short-term diabetes on the parathyroid hormone sensitive rat renal adenylate cyclase: correlation with vitamin D metabolism. 307 95

Administration of 650 pmol 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] to vitamin D-deficient chicks increased adenylate cyclase activity in the basolateral membrane of duodenal epithelial cells within 24 h. This increase in enzymatic activity was accompanied by an increase in calmodulin content of the basolateral membrane. Although neither exogenously added calmodulin (up to 10 micrograms/ml) nor calcium (from 10(-7)-10(-5) M) stimulated enzyme activity, calmodulin antagonists trifluoperazine, W7, and W13 inhibited it. When calmodulin content, adenylate cyclase activity, and alkaline phosphatase activity were measured in cells sequentially eluted from the tip to the base of the villus, cells from the midregion and base had the highest calmodulin content and adenylate cyclase activity, whereas alkaline phosphatase activity (a brush border membrane enzyme) was highest in cells eluted from the tip. Adenylate cyclase activity was increased by 1,25-(OH)2D3, particularly in cells from the midvillus. Our results indicate that the response of adenylate cyclase activity to 1,25-(OH)2D3 varies along the villus and suggest that calmodulin may be involved.
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PMID:Stimulation by 1,25-dihydroxyvitamin D3 of adenylate cyclase along the villus of chick duodenum. 378 May 39

To investigate the possible role of prostaglandin E2 (PGE2) in modulating the actions of PTH and calcitonin (CT) in the kidney, the effects of PGE2 were examined on the in vivo conversion of [3H]25-hydroxyvitamin D3 to [3H]1,25-dihydroxyvitamin D3 ([3H]1,25-(OH)2D3) in vitamin D-deficient thyroparathyroidectomized (T-PTX) rats and on the urinary excretion of phosphate (Pi) in vitamin D-replete T-PTX rats in the presence of either PTH or CT. Plasma accumulation of [3H] 1,25-(OH)2D3 increased from 12.2 +/- 0.6 pmol/100 ml in controls to 19.5 +/- 1.1 (P less than 0.01) by 20 micrograms/h PGE2 to 29.8 +/- 1.8 (P less than 0.001) by 7.5 U/h PTH, and to 23.3 +/- 0.7 (P less than 0.01) by 500 mU/h CT. Administration of PGE2 inhibited CT-stimulated accumulation of 1,25-(OH)2D3 to levels not different from those by PGE2 alone (17.8 +/- 1.0 pmol/100 ml). In contrast, PGE2 had no effect on PTH-stimulated 1,25-(OH)2D3 accumulation. PTH and CT caused an increase in urinary Pi excretion and a decrease in plasma Pi levels. PGE2 abolished the effects of CT, but not of PTH, on both urinary Pi excretion and plasma Pi levels. Administration of PGE2 alone caused no significant changes in plasma Pi levels and only minimal increase in urinary Pi excretion. PGE2 did not suppress urinary cAMP excretion stimulated by CT. These results demonstrate that PGE2 specifically suppresses the effects of CT to stimulate synthesis of [3H]1,25-(OH)2D3 from [3H]25-hydroxyvitamin D3 and to inhibit tubular reabsorption of Pi without affecting urinary cAMP excretion. Since CT appears to stimulate 1 alpha-hydroxylase and inhibit Pi reabsorption in proximal tubules, nephron segments devoid of CT-sensitive adenylate cyclase, these data suggest that PGE2 modulates the actions of CT, but not of PTH, on proximal tubular functions.
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PMID:Inhibition by prostaglandin E2 of renal effects of calcitonin in rats. 385 98

Three patients with hypercalcemia associated with malignant lymphoma and elevations in plasma 1,25-dihydroxyvitamin D [1,25-(OH)2D] are described. In addition to the elevation of circulating 1,25-(OH)2D, these three patients were characterized by suppressed immunoreactive PTH levels and urinary cAMP excretion, elevated fasting urinary excretion of calcium, and absence of adenylate cyclase-stimulating activity in the tumor extracts. Bone marrow biopsy and skeletal radionuclide scans were negative for lymphoma in two patients. Surgical excision of a solitary splenic lymphoma in one patient and medical therapy in another patient resulted in rapid normalization of the serum calcium and plasma 1,25-(OH)2D levels. These findings confirm an earlier observation that elevated plasma levels of 1,25-(OH)2D may occur in certain patients with lymphoma and suggest that this vitamin D metabolite may act as a humoral or systemic mediator of hypercalcemia. Proof that this is the case and identification of the source of 1,25-(OH)2D production will require further study.
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PMID:Elevations in circulating 1,25-dihydroxyvitamin D in three patients with lymphoma-associated hypercalcemia. 387 Oct 92

We examined characteristics of circulating PTH in three patients with pseudohypoparathyroidism type I. All patients were normocalcemic while receiving vitamin D therapy at the time of study. In all three, immunoreactive PTH levels were elevated, whereas bioactive levels were low or low normal. Analysis of plasma immunoreactivity by high performance liquid chromatography revealed a relative increase in hydrophobic moieties compared to patterns in patients with other hyperparathyroid states. Plasma or serum from these patients inhibited the stimulatory action of exogenous bovine PTH in an in vitro renal cytochemical bioassay and an in vitro renal adenylate cyclase assay. Such inhibition persisted after partial reduction, in one patient, of circulating immunoreactive PTH levels by an acute calcium challenge. Patient plasma did not bind bioactive 125I-labeled PTH in vitro. The results demonstrate abnormal persistence of elevated immunoreactive PTH levels in normocalcemic patients with pseudohypoparathyroidism, indicate that this circulating hormone may be altered, and suggest that a defect in PTH release and/or metabolism may accompany the other biochemical abnormalities known to occur in this disorder.
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PMID:Examination of circulating parathyroid hormone in pseudohypoparathyroidism. 400 9

Bone cells isolated from mouse calvariae by a sequential digestion procedure have many osteoblast characteristics: they respond to PTH and prostaglandin E2 by activation of adenylate cyclase but not to calcitonin, they stain for alkaline phosphatase and they make only type I collagen. In confluent monolayer culture, they do not secrete collagenase in appreciable quantities, unless stimulated with resorptive substances such as PTH, prostaglandin E2, 1,25(OH)2 vitamin D-3 and monocyte-conditioned medium. This suggests they play a direct role in bone resorption.
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PMID:Mouse osteoblasts synthesize collagenase in response to bone resorbing agents. 609 72

The objective of this investigation was to determine whether physiological levels of vitamin D and its metabolites have part of their mechanisms of action through stimulation of guanylate cyclase (EC 4.6.1.2). These sterols enhanced both soluble and particulate guanylate cyclase activities as well as cGMP levels two- to threefold in human and rat tissues. At a concentration of 1 nM, 1,25(OH)2D3 greater than 25(OH)D3 greater than vitamin D3 greater than 24,25(OH)2D3 = 25,26(OH)2D3 = vitamin D2. Dose-response curves revealed that maximal stimulation of guanylate cyclase by these sterols was at 1 nM and that there was no augmented guanylate cyclase activity at 0.01 nM. The precursors of vitamin D, cholesterol and 7-dehydrocholesterol, had no effect on guanylate cyclase activity. The activation of guanylate cyclase activity by the vitamin D sterols required the presence of manganese ion. Calcium was not as efficient as manganese in optimizing basal or hormone-stimulated guanylate cyclase activity. Vitamin D and its metabolites failed to stimulate adenylate cyclase (EC 4.6.1.1) activity. The data in this investigation suggest that guanylate cyclase may play a role in the mechanism of action of vitamin D at the cellular level.
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PMID:Cation-dependent vitamin D activation of human renal cortical guanylate cyclase. 614 31

Cell culture, a powerful tool for the study of cell biology, offers advantages for the study of renal cell function. Epithelial cells derived from a variety of organs, including the kidney, form oriented epithelial sheets in culture that have many structural characteristics (microvilli, tight junctions) of epithelia in situ. There is evidence of transepithelial transport of salt and water by cells of two lines (MDCK and LLC-PK1) derived from mammalian kidney. LLC-PK1 cells may also manifest the glucose transport system of the proximal tubule. Cells of both lines have adenylate cyclase activity sensitive to hormones. Two lines of cells derived from toad urinary bladder form epithelia with a high transepithelial resistance and transport sodium actively from apical to basolateral surface. The rate of sodium transport in both lines is stimulated by cyclic AMP and by aldosterone. There are important differences in the characteristics of the response of the two lines to aldosterone as well as in their sensitivity to inhibition of sodium transport by amiloride. These differences may lead to new insights regarding the molecular events in the response to aldosterone and in the inhibitory action of amiloride. Cultures of kidney cells have also been used effectively to study the biosynthesis of the hormonal derivative of vitamin D and to study prostaglandin production. In addition, cell culture is ideally suited for study of the developmental biology of the kidney.
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PMID:Studies of renal cell function using cell culture techniques. 624 76

Rats fed a diet deficient in both vitamin D and Ca2+ exhibited a greater depression of the renal parathyroid hormone (PTH)-dependent adenylate cyclase than was observed in rats fed diets deficient in either vitamin D or calcium. Total serum Ca2+ was decreased from a control level of 11.2 mg/dl to 8.5 mg/dl in rats fed the diet deficient in calcium alone, and to 5.4 mg/dl in rats fed the diet deficient in vitamin D. Serum calcium was decreased further to 4.3 mg/dl in rats fed the diet deficient in both vitamin D and Ca2+. Serum immuno-reactive PTH was significantly elevated over control levels when rats were fed the test diets; however, there were no significant differences between the elevated levels in the three experimental groups. Repletion of rats deficient in vitamin D only with a single oral dose of 3200 I.U. vitamin D-2 resulted in restoration of serum calcium to normal levels, a return of serum PTH to the control state, and an associated increase in PTH-dependent adenylate cyclase activity to the control level by 72 h. Repletion of rats deficient in both vitamin D and Ca2+ with the same dose of vitamin D-2 raised serum Ca2+ to 7.2 mg/dl by 72 h, but did not cause a reduction in circulating PTH, nor did it result in any significant improvement in the responsiveness of the membrane adenylate cyclase to PTH. These results suggest that elevated PTH is a factor in the down regulation of the PTH-dependent adenylate cyclase, but do not rule out a role for calcium as a regulatory factor.
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PMID:Renal parathyroid hormone-dependent adenylate cyclase activity after repletion of vitamin D-deficient rats with vitamin D-2. 625 4


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