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)

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

Despite extensive study since the first report of familial benign hypercalcemia (FBH, or hypocalciuric hypercalcemia) in 1972, there is no evidence of the specific abnormal gene product. FBH is highly suitable for either a candidate gene or a reverse genetics approach to localizing the genetic abnormality, because it is inherited in an autosomal dominant pattern, is highly penetrant, does not affect survival, and can be diagnosed in families with readily available measurements. Importantly, several candidate genes have been cloned and mapped. Therefore, we collected blood samples and extracted leukocyte DNA from 94 members of 4 families with well documented FBH (44 affected, 45 unaffected, and 5 unclassifiable). We digested the DNA samples with various restriction endonucleases, conducted standard Southern blotting, and searched for restriction fragment length polymorphisms for the following candidate genes (probe names in parentheses): multiple endocrine neoplasia (MEN) type 1 (pMCMP.1, pHBI59, p3C7, and pTHH26), MEN 2a (MCK2 and cTB14.34), basic fibroblast growth factor (pHFL1-7), (Ca2+,Mg2+)ATPase isoform 4 (hPMCA4), membrane Na/Ca exchanger (cNC28 M-A), PTH (pPTH-LF), and calbindin-D28K (pSKCalb). In addition, we used the anonymous variable number tandem repeat marker pYNH24 to verify pedigree structures by excluding misinheritances. Data were analyzed using the Linkage program. For none of the genes was there significant linkage with the FBH trait; logarithm of odds scores ranged from -1.3 to -26.0 at a recombination fraction of 0.001, and from 0.6 to -5.6 at a recombination fraction of 0.10. We conclude that FBH is unrelated to the MEN syndromes and is not caused by mutations in any of the calcium-regulating or -binding proteins or growth factors studied thus far.
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PMID:Genetic linkage analysis in familial benign hypercalcemia using a candidate gene strategy. I. Studies in four families. 151 76

Computer simulations of transcellular Ca2+ transport in enterocytes were carried out using the simulation program SPICE. The program incorporated a negative-feedback entry of Ca2+ at the brush-border membrane that was characterized by an inhibitor constant of 0.5 microM cytosolic Ca2+ concentration ([Ca2+]). The basolateral Ca(2+)-ATPase was simulated by a four-step mechanism that resulted in Michaelis-Menten kinetics with a Michaelis constant of 0.24 microM [Ca2+]. The cytosolic diffusion of Ca2+ was simulated by dividing the cytosol into 10 slabs of equal width. Ca2+ binding to calbindin-D9K was simulated in each slab, and diffusion of free Ca2+, free calbindin, and Ca(2+)-laden calbindin was simulated between each slab. The cytosolic [Ca2+] of the simulated cells was regulated within the physiological range. Calbindin-D9K reduced the cytosolic [Ca2+] gradient, increased Ca2+ entry into the cell by removing the negative-feedback inhibition of Ca2+ entry, increased cytosolic Ca2+ flow, and increased the efflux of Ca2+ across the basolateral membrane by increasing the free [Ca2+] immediately adjacent to the pump. The enhancement of transcellular Ca2+ transport was nearly linearly dependent on calbindin-D9K concentration. The values of the dissociation constant (Kd) for calbindin-D9K were previously obtained experimentally in the presence and absence of KCl. Calbindin with the Kd obtained in the presence of KCl enhanced the simulated Ca2+ transport more than with the Kd obtained in the absence of KCl. This result suggests that the physiological Kd of calbindin is optimal for the enhancement of transcellular Ca2+ transport. The simulated Ca2+ flow was less than that predicted from the "near-equilibrium" analytic solution of the reaction-diffusion problem.
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PMID:Role of facilitated diffusion of calcium by calbindin in intestinal calcium absorption. 153 38

The mechanism of vitamin D-dependent intestinal calcium transport has been explored in experimental animals in vivo and in vitro with the aid of pharmacologic agents that inhibit steps in the translocation process. Glucocorticoids in vivo, but not in vitro, inhibit the mucosal-to-serosal flux (Jms) of calcium and thus reduce net calcium absorption. Chronic metabolic acidosis inhibits calcium transport in vivo through inhibition of 1,25-dihydroxycholecalciferol [1,25(OH)2D3] production and by a direct effect in vitro on the enterocyte to decrease calcium Jms. Cellular functions that may be involved in the transport process have been inhibited in vitro, including brush border calcium uptake by calcium channel blockers; calmodulin-dependent Ca-activated ATPase by trifluoperazine; calcium binding to vitamin D-dependent calcium-binding protein (CaBP, calbindin) by theophylline and acidic lysosomal vesicle function by quinacrine, chloroquine and ammonium chloride. The results of these studies demonstrate the consequences of selectively inhibiting steps thought to be involved in calcium transport and suggest new directions for further research in elucidating mechanisms of cellular calcium transport.
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PMID:The use of pharmacologic agents to study mechanisms of intestinal calcium transport. 154 31

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

In order to further test the validity of the vesicular transport model of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-stimulated intestinal calcium absorption, dose-response studies were undertaken. Using previously established methodology for subcellular fractionation following 45Ca absorption from in situ ligated duodenal loops, radionuclide levels were found to increase gradually in endocytic vesicles prepared from 1,25(OH)2D3-treated (+D) chicks relative to controls (-D) achieving a plateau at greater than or equal to 260 pmol seco-steroid. By comparison, lysosomal 45Ca levels increased more readily, having +D/-D ratios of 1.88 +/- 0.35, 2.21 +/- 0.05, 2.17 +/- 0.88, 2.31 +/- 0.25, and 2.15 +/- 0.47 after 0.0104, 0.052, 0.26, 1.3, or 6.5 nmol of 1,25(OH)2D3, respectively. Net intestinal calcium absorption, as judged by appearance of 45Ca in the serum for the same range of doses, rose gradually to a plateau value at greater than or equal to 260 pmol. Since lysosomal 45Ca levels were maximally increased at 1,25(OH)2D3 doses lower than those required for fully stimulated transport, it was concluded that lysosomes are still candidates for cellular calcium carriers, but that other elements of the transport pathway are required. Analyses of gradient fractions for calbindin-D28K (the vitamin D-induced calcium binding protein), and potential 1,25(OH)2D3-mediated changes in vesicular ATPase (microtubule motive power for transcellular delivery of calcium) failed to identify the missing components.
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PMID:1,25-Dihydroxyvitamin D3-mediated vesicular calcium transport in intestine: dose-response studies. 253 14

The intestinal absorption of calcium is certainly a complex process, dependent on several factors of which vitamin D, via 1,25(OH)2D3, is the major controlling hormone. The efficiency of calcium absorption is a function of calcium status and calcium need. As the body's demand for calcium increases, the process commonly termed, adaptation, is activated in which the synthesis of 1,25(OH)2D3 from precursor is increased, resulting in the stimulation of the rate of calcium absorption. The increased demand for calcium might result from the ingestion of a diet deficient in calcium, from growth, pregnancy, lactation and egg shell formation in the laying hen. Accomapanying the change in calcium absorptive efficiency are molecular modifications of the transporting enterocytes, some mentioned herein and elsewhere (Wasserman & Chandler, 1985; Wasserman, 1980; Wasserman et al., 1984). Highly correlated with the rate of calcium absorption under a wide variety of conditions is the concentration of the vitamin D-induced calcium-binding protein, calbindin-D28K (avian type) and calbindin-D9K (mammalian intestinal type). The role of calbindin-D in this transport process is not precisely known but is considered to act at the present time as a cytosolic facilitator of Ca2+ diffusion from the brush border membrane to the basolateral membrane. In addition to the induction of calbindin-D synthesis, 1,25(OH)2D3 exerts other effects on the intestinal epithelium that can have consequences on the calcium absorptive process. Some of these effects are summarized in Figure 14. Vitamin D-dependent reactions might be either direct effects of 1,25(OH)2D3 or indirect effects due to elevated intracellular Ca2+ concentrations. These include changes in the fluidity of the brush border membrane, an increase in microvillar alkaline phosphatase-low affinity Ca-activated ATPase activity, an association of calmodulin with the 105 kD brush border cytoskeletal protein and, following calbindin D synthesis, the binding of calbindin D to a 60 kD brush border protein and to microtubules. The latter has been suggested to be related to the proposed transfer of Ca2+ by an endocytotic-exocytotic mechanism. In addition, a vitamin D-dependent intestinal membrane calcium-binding protein has been identified (Kowarski & Schachter, 1980). Playing into this multi-component system is a stimulation of cyclic nucleotide synthesis by 1,25(OH)2D3 which, through activation of cyclic nucleotide-dependent protein kinases, might modify membrane Ca2+ "channels" by phosphorylation reactions.4+ Intracellular organelles, i.e., the endoplasmic reticulum, mitochondria, the Golgi apparatus, are potent sequesters of Ca2+ and could contribute to the protection of the cell from excessively high Ca2+ concentrations by transiently storing absorbed Ca2+.
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PMID:On the molecular mechanism of intestinal calcium transport. 254 94

Renal calcium transport is described as the result of two processes, a paracellular, gradient-dependent process that predominates in most segments of the nephron and a transcellular, energy-dependent step that characterizes calcium transport in the distal convoluted tubule (DCT). Transcellular calcium transport involves entry into the DCT cell, possibly via channels, intracellular movement which appears to be facilitated by the presence of the vitamin D-dependent, cytosolic calcium-binding protein (CaBPr, calbindin D28k, mol mass approximately 28 kDa), and extrusion via the Ca-ATPase. Although much is known about calcium channels, their presence in renal tissue has only been demonstrated by preliminary studies. Quantitative data on CaBPr content of rat DCT are also unavailable, but theoretical analysis and early experimental values of intracellular self-diffusion of calcium have confirmed the need for an intracellular calcium "ferry," i.e., a molecule like CaBPr to amplify intracellular calcium movement. Available data on the plasma membrane Ca-ATPase are consistent with the extrusion kinetics attributed to the renal Ca-ATPase, but it has not been isolated, nor has its gene been cloned. Regulation and disorders of renal calcium transport are likely to involve one of the three transcellular steps, but indirect regulation by modification of the cell walls and molecules constituting the paracellular pathway cannot be excluded.
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PMID:Renal calcium transport: mechanisms and regulation--an overview. 268 64

The vitamin D-dependent, calcium-binding protein from rat kidney, calbindin D28k (renal CaBP) specifically stimulates Ca,Mg-ATPase activity of human erythrocyte plasma membranes in a dose-dependent, calcium-sensitive manner. This stimulation was about two-fold compared to a three-fold stimulation by calmodulin. The effect was specific since other calcium-binding proteins and low molecular weight proteins did not stimulate Ca,Mg-ATPase activity. Renal CaBP did not stimulate cyclic nucleotide phosphodiesterase at concentrations greater than those which stimulated Ca,Mg-ATPase activity. This is the first report of a specific in vitro effect of renal CaBP on an enzyme system.
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PMID:Specific in vitro activation of Ca,Mg-ATPase by vitamin D-dependent rat renal calcium binding protein (calbindin D28K). 294 79

We describe a new technique for immunohistochemical and enzyme-histochemical double staining using confocal laser scanning microscopy in the reflection mode. As an example, we investigated the immunoreactivity for Spot 35-calbindin-D28K, a vitamin D-dependent calcium binding protein, and the enzyme activity for Ca(2+)-ATPase in the rat kidney. The lead precipitation method for Ca(2+)-ATPase was initially used to process kidney slices. Each specimen was then dehydrated and embedded in a water soluble resin. Thin sections were cut from the resin block, and an indirect immunocolloidal gold method with silver enhancement for Spot 35-calbindin-D28K antigen was carried out on the glass slides. Results were then observed by confocal laser scanning microscopy in the reflection mode. The three-dimensional distribution of the reaction products was detected by serial optic slice images. Lead phosphate particles, which represented the location of Ca(2+)-ATPase, were distributed deep in the section. The most intense signals from the silver particles were detected from the surface slice of the section. A stereoscopic image generated from the serial optic slices clearly showed the differences in their distribution.
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PMID:A new histochemical double-stain method using three-dimensional analysis with confocal laser scanning microscopy. 753 68


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