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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Total renal ischemia for various time intervals (0-50 min) resulted in the rapid and duration-dependent redistribution of polarized membrane lipids and proteins in renal proximal tubule cells. Following only 15 min of ischemia, apical membrane enrichment of NaK-ATPase, normally a basolateral membrane (BLM) enzyme, had increased (1.6 +/- 0.6 vs. 2.9 +/- 1.2, P less than 0.01). In vivo histochemical localization of NaK-ATPase showed reaction product throughout the apical microvillar region. PTH-stimulatable adenylate cyclase, another BLM protein, was also found in ischemic but not control apical membrane fractions. One dimensional SDS-PAGE showed four bands, present in control BLM and ischemic apical membranes, which could not be found in control apical membrane fractions. Immunohistochemical localization of leucine aminopeptidase (LAP) showed the enzyme was limited to the apical domain in control cells. Following ischemic injury (50 min), LAP staining could be seen within the cell and along the BLM. Following 24 hr of reperfusion, the BLM distribution of LAP was further enhanced. With cellular recovery from ischemic injury (5 days), LAP was again only visualized in the apical membrane. Duration-dependent alterations in apical and BLM lipids were also observed. Apical sphingomyelin and phosphatidylserine and the cholesterol-to-phospholipid ratio decreased rapidly while apical phosphatidylcholine and phosphatidylinositol increased. Taken together, these results indicate renal ischemia causes rapid duration-dependent reversible loss of surface membrane polarity in proximal tubule cells.
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PMID:Characterization of ischemia-induced loss of epithelial polarity. 246 76

The pathogenesis of familial benign hypercalcemia (FBH) is unknown. Possible explanations for the disorder include a set-point error in parathyroid gland regulation and intrinsic renal hyperreabsorption of calcium. Thus, FBH may involve an alteration in cellular calcium transport, especially in renal and parathyroid cells. A primary mediator of cellular calcium transport is (Ca2+,Mg2+)ATPase. Therefore, we examined in detail the kinetics of (Ca2+,Mg2+)ATPase activity in erythrocyte plasma membranes from 11 patients with FBH from 7 families, 5 patients with untreated primary hyperparathyroidism, and equal numbers of age- and sex-matched normal subjects. (Ca2+,Mg2+)ATPase activity was measured in isolated membranes as a function of free calcium (0.05-300 mumol/L) in the presence or absence of calmodulin (600 nmol/L) and as a function of calmodulin (0-1800 nmol/L). We found no significant differences in calcium- or calmodulin-dependent (Ca2+,Mg2+)ATPase kinetics between patients with FBH or primary hyperparathyroidism and their age- and sex-matched normal subjects. None of the kinetic parameters was correlated with serum calcium or serum PTH values. We postulate that a mechanism other than a global defect in (Ca2+,Mg2+)ATPase activity is responsible for the hypercalcemia in patients with FBH.
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PMID:Kinetics of erythrocyte plasma membrane (Ca2+, Mg2+)ATPase in familial benign hypercalcemia. 252 97

We have established a perifusion system to monitor free cytosolic calcium concentrations ([Ca2+]i) in mouse kidney slices, which presumably reflects in vivo status more accurately than renal cells in culture, by means of the fluorescent calcium indicators quin-2 and fura-2. An increase in the extracellular calcium concentrations from 0 (no added Ca2+) to 3.0 mM resulted in an increase in [Ca2+]i from 52 to 239 nM. Replacement of 118 mM of extracellular Na+ with choline, or the addition of ouabain, an inhibitor of Na+,K+-ATPase, at 10(-6) M in the perfusate caused an increase in [Ca2+]i from 161 +/- 13 to 873 +/- 78 nM (n = 10) and 161 +/- 13 to 395 +/- 68 nM (n = 4), respectively, suggesting the possible existence of a Na+,Ca2+ exchange mechanism in the kidney slice. We further examined the effects of PTH on [Ca2+]i mobilization in the kidney. Both human PTH-(1-34) and hPTH-(1-84) increased [Ca2+]i within 60 s at physiologic concentrations of 10(-11)-10(-9) M in a dose-dependent manner. On the other hand, an increase in intracellular cAMP in the slice was also detected above 3 X 10(-9) M hPTH-(1-34) [base 2.1 +/- 0.4 pmol/mg, 3.2 +/- 0.6 pmol/mg (p less than 0.05 versus control values) 5 minutes after the application of 3 X 10(-9) M hPTH-(1-34) and 17.3 +/- 4.3 pmol/mg (p less than 0.05 versus control values) 3 X 10(-8) M hPTH-(1-34), mean +/- SEM, n = 7, p less than 0.05 versus control values].(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Parathyroid hormone control of free cytosolic Ca2+ in the kidney. 284 98

The effect of [Nle8,18,Tyr34]bPTH-(1-34)amide on renal plasma membrane adenylate cyclase, in the presence of 0.1 mM guanylylimidodiphosphate was measured in rat, chicken, frog and trout. All species showed an enrichment of at least 8-fold (relative to homogenate) in the marker enzyme Na+,K+-ATPase. A significant dose-dependent adenylate cyclase stimulation was found in frog, with affinity values similar to those of rat and chicken (ED50=8, 10 and 3 nM, respectively), but not in trout. The frog response was specific since [Nle8,18,Tyr34]bPTH-(3-34)amide strongly inhibited the agonist-stimulated enzyme. These results suggest the existence of a PTH-like substance in anurans acting via cyclic AMP formation in the kidney.
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PMID:Parathyroid hormone stimulation of renal adenylate cyclase in various vertebrate species: evidence for an effect in the frog. 289 Apr 72

PTH enhances entry of calcium into RBC, stimulates their Ca ATPase and increases osmotic fragility. The effect on the latter occurs only in the presence of calcium. The mechanisms of action of PTH and those mediating their increased calcium influx into RBC are not evident. It is possible that calcium, PTH or both affects phospholipid turnover of RBC and results in production of ionophoric compounds such as phosphatidic acid which in turn allows calcium movement. The present study examined the effect of calcium (1 mM), 1-84 PTH (50 U/ml) and calcium and PTH on phospholipid contents and 32P incorporation into phosphoinositides of human RBC and RBC ghosts. Calcium produced significant decrements in 32P incorporation into phosphatidylinositol, di- and triphosphatidylinositol and an increase into phosphatidic acid. PTH decreased the 32P into phosphatidylinositol only. Both PTH or calcium caused a significant increase in RBC content of phosphatidylserine. The data show that calcium alone alters phospholipid turnover of RBC and such an effect may mediate the PTH-induced calcium influx. Alternatively, PTH may enhance entry of calcium into RBC independent of the effect of calcium on phospholipid turnover and the increase in cytosolic calcium would then alter phospholipid turnover which in turn would further facilitate the effect of PTH on calcium influx. The increase of phosphatidylserine by PTH may increase rigidity of RBC membrane and enhance osmotic fragility.
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PMID:Calcium, parathyroid hormone and phospholipid turnover of human red blood cells. 298 43

High affinity (Ca2+ + Mg2+)ATPase activity was demonstrated in proximal tubule basolateral membranes (BLM) obtained from canine kidney. The Km of the enzyme for free Ca2+ was 0.12 +/- 0.02 microM, and at 3 microM free Ca2+, the enzyme reached its maximal velocity. To evaluate hormonal regulation of this enzyme, we studied the in vitro effects of several polypeptide hormones on enzyme activity. We measured the effects of insulin and human (h) PTH-(1-34) and their inactive analogs desoctapeptide insulin, bovine (b) PTH-(3-34), and oxidized hPTH-(1-34); insulin-like growth factors (IGFs) I and II; calcitonin; and the common cellular mediator for PTH and calcitonin, cAMP. At 0.1 microM free Ca2+, insulin (25-100 microU/ml) increased (Ca2+ + Mg2+)ATPase activity in a dose-dependent manner by 35-52% (P less than 0.01) and by 8-13% (P less than 0.05 to P less than 0.01) at a 3-microM free Ca2+ concentration; hPTH-(1-34) PTH (10(-9)-10(-7) M) increased the enzyme activity at a free Ca2+ concentration of 0.1 microM by 13-25% (P less than 0.05 to P less than 0.01). IGF-I increased (Ca2+ + Mg2+)ATPase activity by 40% (P less than 0.05) at 0.1 microM free Ca2+ at high peptide concentrations (10 ng/ml). No effect was obtained at 2 ng/ml IGF-I. cAMP (10(-7)-10(-4) M) stimulated enzyme activity by 18-27% (P less than 0.05 to P less than 0.02) at 0.1 microM Ca2+ and by 8-12% (P less than 0.05 to P less than 0.01) at 3 microM Ca2+. The effects of insulin and cAMP on (Ca2+ + Mg2+)ATPase activity were additive. No effect on the enzyme activity was obtained by the inactive analogs desoctapeptide insulin, bPTH-(3-34), and oxidized hPTH-(1-34), or by calcitonin or IGF-II. The data suggest that insulin and PTH have a specific stimulatory effect on (Ca2+ + Mg2+)ATPase activity in canine kidney proximal tubular BLM. While the insulin action is independent of cAMP, a role of cAMP in the regulatory effect of PTH on this enzyme cannot be ruled out. The direct stimulatory effect of insulin and PTH on (Ca2+ + Mg2+)ATPase in canine kidney proximal tubular BLM suggests that these hormones mediate their cellular effects in part by changes in cellular calcium homeostasis.
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PMID:Hormonal regulation of (Ca2+ + Mg2+)ATPase activity in canine renal basolateral membrane. 302 12

We have previously found that high extracellular calcium (Ca++) concentrations inhibit PTH release in association with a threefold to fourfold rise in cytosolic Ca++ concentration. Recent data have also shown that low extracellular potassium (K+) concentration or ouabain also inhibits PTH release to an extent comparable to that seen with high Ca++ and produce a marked rise in the intracellular sodium (Na+) content. These results suggested that low K+ and ouabain might modulate PTH release through increases in cytosolic Ca++ related to alterations in Na+-Ca++-exchange. In the present studies, we have examined further the mechanism(s) by which inhibition of the Na+-K+-ATPase regulates PTH release. Exposure of cells loaded with the Ca++-sensitive dye QUIN-2 to low K+ produced a 10% to 17% increase in cytosolic Ca++ at 0.5 to 1.0 mmol/L extracellular Ca++, which was statistically significant only at 0.75 mmol/L Ca++. In contrast, low K+ caused a statistically significant decrease in cytosolic Ca++ at 1.5 to 2 mmol/L Ca++, while ouabain lowered cytosolic Ca++ significantly by 23% to 46% at all Ca++ concentrations examined (0.5 to 2 mmol/L). Low K+ or ouabain had no effect on cellular levels of ATP or GTP or intracellular pH measured using the pH-sensitive dye BCECF [2', 7'-bis(carboxyethyl)-5,6-carboxyfluorescein]. The inhibition of secretion by low K+ or ouabain, unlike that due to high extracellular Ca++, was not reversed by TPA (12-O-tetradecanoyl phorbol 13-acetate), an activator of protein kinase C. Low K+ did produce a modest (30% to 40%) lowering of agonist-stimulated but not basal cAMP content.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ouabain and low extracellular potassium inhibit PTH secretion from bovine parathyroid cells by a mechanism that does not involve increases in the cytosolic calcium concentration. 302 50

Primary cultures of rabbit-kidney epithelial cells derived from purified proximal tubules were maintained without fibroblast overgrowth in a hormone-supplemented serum-free medium (Medium RK-1). A hormone-deletion study indicated that the primary cultures derived from purified rabbit proximal tubules required all of the three supplements in Medium RK-1 (insulin, transferrin, and hydrocortisone) for optimal growth but did not grow in response to EGF and T3. In contrast, the epithelial cells in primary cultures derived from an unpurified preparation of rabbit kidney tubules and glomeruli grew in response to EGF and T3, as well as insulin, transferrin, and hydrocortisone. These observations suggest that kidney epithelial cells derived from different segments of the nephron grow differently in response to hormones and growth factors. Differentiated functions of the primary cultures derived from proximal tubules were examined. Multicellular domes were observed, indicative of transepithelial solute transport by the monolayers. The proximal tubule cultures also accumulated alpha-methylglucoside (alpha-MG) against a concentration gradient. However, little or no alpha-MG accumulation was observed in the absence of Na+. Metabolic inhibitor studies also indicated that alpha-MG uptake by the primaries is an energy-dependent process, and depends upon the activity of the Na+/K+ ATPase. Phlorizin at 0.1 mM significantly inhibited 1 mM alpha-MG uptake whereas 0.1 mM phloretin did not have a significant inhibitory effect. Similar observations have been made concerning the Na+-dependent sugar-transport system located on the lumenal side of the proximal tubule, whereas the Na+-independent sugar transporter on the peritubular side is more sensitive to inhibition by phloretin than phlorizin. The cultures also exhibited PTH-sensitive cyclic AMP synthesis and brush-border enzymes typical of proximal cells. However, the activities of the enzymes leucine aminopeptidase, alkaline phosphatase, and gamma-glutamyl-transpeptidase were lower in the cultures than in purified proximal-tubule preparations from which they are derived.
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PMID:Characterization of primary rabbit kidney cultures that express proximal tubule functions in a hormonally defined medium. 629 32

We have previously reported that stimulated release of calcium (Ca) from bone is a sodium-dependent process. Partial support for this conclusion came from the observation that ouabain inhibited stimulated bone resorption as a result of inhibition of the Na,K-ATPase in bone. We now present additional supporting evidence from the results of experiments using vanadate, an ion known to inhibit the activity of Na,K-ATPase. Vanadate inhibited stimulated bone resorption in neonatal mouse calvaria. Inhibition occurred in a dose-dependent manner, and ortho-vanadate was 3-fold more potent than meta-vanadate. Ortho-vanadate was equally effective against several different stimulators of resorption, including PTH, prostaglandin E2, and 1,25-dihydroxycholecalciferol. PTH-stimulated bone resorption was inhibited with a Ki of about 9 microM. Stimulated Ca release was completely blocked whether vanadate was added at zero time or 24 h after the addition of a resorption-stimulating agent. Because the responses to vanadate were similar to those observed with ouabain, we conclude that vanadate is probably acting to inhibit stimulated resorption via inhibition of the Na,K-ATPase in bone.
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PMID:Inhibition of stimulated bone resorption by vanadate. 630 36

We have compared the effects of the cardiac glycoside ouabain on [3H]ouabain binding, 86Rb uptake, cellular sodium and potassium, and PTH secretion in dispersed bovine parathyroid cells. [3H]ouabain binds reversibly to a single class of binding sites with an affinity of 6.1 X 10(-8) M and a binding capacity of 5.8 X 10(5) sites/cell. Ouabain also inhibits the uptake of 86Rb, an analog of K, by 90% with half-maximal inhibition at 7.2 X 10(-8) M. There is a concomitant, ouabain-induced increase in cellular sodium and a reduction in cellular potassium. The half-maximal effect on cellular monovalent cations takes place at 1.4 X 10(-7 M ouabain. Finally, ouabain causes a dose- and time-dependent inhibition of low calcium-stimulated PTH secretion. This inhibition does not require extracellular calcium; half-maximal inhibition occurs at 1.1 X 10(-7) M ouabain. These results show that dispersed bovine parathyroid cells contain abundant binding sites for ouabain, a known inhibitor of Na+-K+-ATPase. Moreover, the ouabain-induced reduction in 86Rb uptake and alterations in cellular sodium and potassium support an inhibition of this enzyme in parathyroid cells by the cardiac glycoside. Finally, the close correspondence between ouabain binding and effects on Rb uptake, cellular monovalent cations, and PTH release suggest a role for Na+-K+-ATPase per se or for monovalent cations in PTH secretion. A change in sodium-calcium exchange due to the elevation in cellular sodium is a potential mechanism by which ouabain might inhibit PTH secretion.
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PMID:Effects of ouabain on [3H]ouabain binding, 86Rb uptake, cellular sodium and potassium, and parathyroid hormone secretion in dispersed bovine parathyroid cells. 686 9


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