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)

The Na(+)-retaining hormone aldosterone increases the cell-surface expression of the luminal epithelial sodium channel (ENaC) and the basolateral Na(+) pump (Na,K-ATPase) in aldosterone-sensitive distal nephron cells in a coordinated fashion. To address the question of whether aldosterone-induced serum and glucocorticoid-regulated kinase-1 (SGK1) might be involved in mediating this regulation of Na,K-ATPase subcellular localization, similar to that of the epithelial Na(+) channel (ENaC), we co-expressed the Na,K-ATPase (rat alpha 1- and Xenopus laevis beta 1-subunits) and Xenopus SGK1 in Xenopus oocytes. Measurements of the Na(+) pump current showed that wild-type SGK1 increases the function of exogenous Na,K-ATPase at the surface of Xenopus oocytes. This appeared to be secondary to an increase in Na,K-ATPase cell-surface expression as visualized by Western blotting of surface-biotinylated proteins. In contrast, the functional surface expression of two other exogenous transporters, the heterodimeric amino acid transporter LAT1-4F2hc and the Na(+)/phosphate cotransporter NaPi-IIa, was not increased by SGK1 co-expression. The total pool of exogenous Na,K-ATPase was increased by the co-expression of SGK1, and similarly also by ENaC co-expression. This latter effect depended on the [Na(+)] of the buffer and was not additive to that of SGK1. When the total Na,K-ATPase was increased by ENaC co-expression, SGK1 still increased Na,K-ATPase cell-surface expression. These observations in Xenopus oocytes suggest the possibility that SGK1 induction and/or activation could participate in the coordinated regulation of Na,K-ATPase and ENaC cell-surface expression in the aldosterone-sensitive distal nephron.
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PMID:SGK1 increases Na,K-ATP cell-surface expression and function in Xenopus laevis oocytes. 1471 89

The semicircular canal duct (SCCD) epithelium is a vestibular epithelial domain that was recently shown to actively contribute to endolymph homeostasis by Cl(-) secretion under control of beta(2)-adrenergic stimulation. By analogy to other Cl(-) secretory epithelia, we hypothesized that SCCD also provides an active absorptive pathway for Na(+) under corticosteroid control. Measurements of short-circuit current (I(sc)) demonstrated stimulation (7-24 h) by the glucocorticoids hydrocortisone (EC(50) 13 nM), corticosterone (33 nM), prednisolone (70 nM), and dexamethasone (13 nM) over physiologically and therapeutically relevant concentrations and its block by amiloride (IC(50) 470 nM) and benzamil (57 nM), inhibitors of the epithelial sodium channel (ENaC). I(sc) was also partially inhibited by basolateral ouabain and Ba(2+), indicating the participation of Na(+)-K(+)-ATPase and a K(+) channel in Na(+) transport. By contrast, aldosterone stimulated I(sc) only at unphysiologically high concentrations (EC(50) 102 nM). The action of all steroids was blocked by mifepristone (RU-486; K(d) approximately 0.3 nM) but not by spironolactone (K(d) approximately 0.7 microM). Expression of mRNA for the alpha-, beta-, and gamma-subunits of ENaC was demonstrated in the presence and absence of glucocorticoids. These findings are the first to identify SCCD in the vestibular labyrinth as a site of physiologically significant ENaC-mediated Na(+) absorption and osmotically coupled water flux. They further demonstrate regulation of Na(+) transport by natural and therapeutic glucocorticoids. The results provide for the first time an understanding of the therapeutic benefit of glucocorticoids in the treatment of Meniere's disease, a condition that is associated with increased luminal fluid volume.
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PMID:Glucocorticoids stimulate cation absorption by semicircular canal duct epithelium via epithelial sodium channel. 1499 71

Thyrotoxic (hypokalemic) periodic paralysis (TPP) is a frequent complication of thyrotoxicosis among Chinese men. To determine the genetic association of TPP, we studied 97 male TPP patients, 77 Graves' disease patients without TPP, and 100 normal male subjects. Mutations of the voltage-dependent calcium channel (Ca(v)1.1), sodium channel (Na(v)1.4), and potassium channel (K(v)3.4), and association of the microsatellite markers on chromosome 1 in the region of the Na/K-ATPase subunits alpha1, alpha2, and beta1 were studied. None of the TPP patients carried the known mutations in Ca(v)1.1, Na(v)1.4, and K(v)3.4 genes. There was no association of TPP with the microsatellite markers that mapped to 1p13, 1q21-23, and 1q22-25. We detected 12 single nucleotide polymorphisms (SNPs) in Ca(v)1.1 in our population, of which three were novel. Significant differences in the SNP genotype distribution between TPP compared with Graves' disease controls and normal controls were seen at the 5' flanking region nucleotide (nt) -476 (P = 0.02), intron 2 nt 57 (P < 0.01), and intron 26 nt 67 (P < 0.001). Because these SNPs lie at or near the thyroid hormone responsive element, it is possible that they may affect the binding affinity of the thyroid hormone responsive element and modulate the stimulation of thyroid hormone on the Ca(v)1.1 gene.
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PMID:Association of novel single nucleotide polymorphisms in the calcium channel alpha 1 subunit gene (Ca(v)1.1) and thyrotoxic periodic paralysis. 1500 31

Glutamate has been recognized to mediate ischemia-induced neuronal injury in the brain, but the source of extracellular glutamate during ischemic insults remains controversial. We investigated the mechanisms of glutamate release in organotypic cerebrocortical slice cultures prepared from rat neonates, using oxygen glucose deprivation (OGD) as an in vitro ischemia model. Slice cultures were submerged in glucose-free deoxygenated buffer for 20-60 min and glutamate released into the extracellular buffer was quantified. Cell injury was assessed by uptake of propidium iodide 24 h after OGD insult. OGD-induced time-dependent glutamate release and cell injury, both of which were potently inhibited by a sodium channel blocker tetrodotoxin (1 microM). Application of voltage-dependent Ca2+ channel blockers or of an inhibitor of vacuolar-ATPase significantly reduced OGD-induced glutamate release and cell injury. On the contrary, inhibitors of glutamate transporters exacerbated OGD-induced glutamate release and cell injury. Volume sensitive organic anion channel blockers also augmented OGD-induced glutamate release and cell injury. In addition, OGD-induced glutamate release was markedly reduced in neuron-depleted slice cultures that were pretreated with 100 microM NMDA. These results suggest that vesicular release of neuronal origin constitutes a crucial component of extracellular glutamate increase during ischemic insults, which triggers neuronal injury.
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PMID:Mechanisms of oxygen glucose deprivation-induced glutamate release from cerebrocortical slice cultures. 1538 Mar 25

The collecting duct of normal kidney exhibits significant activity of the MEK1/2-ERK1/2 pathway as shown in vivo by immunostaining of phosphorylated active ERK1/2 (pERK1/2). The MEK1/2-ERK1/2 pathway controls many different ion transports both in proximal and distal nephron, raising the question of whether this pathway is involved in the basal and/or hormone-dependent transepithelial sodium reabsorption in the principal cell of the cortical collecting duct (CCD), a process mediated by the apical epithelial sodium channel and the basolateral sodium pump (Na,K-ATPase). To answer this question we used ex vivo microdissected CCDs from normal mouse kidney or in vitro cultured mpkCCDcl4 principal cells. Significant basal levels of pERK1/2 were observed ex vivo and in vitro. Aldosterone and vasopressin, known to up-regulate sodium reabsorption in CCDs, did not change ERK1/2 activity either ex vivo or in vitro. Basal and aldosterone- or vasopressin-stimulated sodium transport was down-regulated by the MEK1/2 inhibitor PD98059, in parallel with a decrease in pERK1/2 in vitro. The activity of Na,K-ATPase but not that of epithelial sodium channel was inhibited by MEK1/2 inhibitors in both unstimulated and aldosterone- or vasopressin-stimulated CCDs in vitro. Cell surface biotinylation showed that intrinsic activity rather than cell surface expression of Na,K-ATPase was controlled by pERK1/2. PD98059 also significantly inhibited the activity of Na,K-ATPase ex vivo. Our data demonstrate that the ERK1/2 pathway controls Na,K-ATPase activity and transepithelial sodium transport in the principal cell and indicate that basal constitutive activity of the ERK1/2 pathway is a critical component of this control.
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PMID:ERK1/2 controls Na,K-ATPase activity and transepithelial sodium transport in the principal cell of the cortical collecting duct of the mouse kidney. 1545 67

Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists have been shown to have significant therapeutic benefits such as desirable glycemic control in type 2 diabetic patients; however, these agents may cause fluid retention in susceptible individuals. Since PPARgamma is expressed selectively in distal nephron epithelium, we studied the mechanism of PPARgamma agonist-induced fluid retention using male Sprague-Dawley rats treated with either vehicle or GI262570 (farglitazar), a potent PPARgamma agonist. GI262570 (20 mg/kg/day) induced a plasma volume expansion. The plasma volume expansion was accompanied by a small but significant decrease in plasma potassium concentration. Small but significant increases in plasma sodium and chloride concentrations were also observed. These changes in serum electrolytes suggested an activation of the renal mineralocorticoid response system; however, GI262570-treated rats had lower plasma levels of aldosterone compared with vehicle-treated controls. mRNA levels for a group of genes involved in distal nephron sodium and water absorption are changed in the kidney medulla with GI262570 treatment. In addition, due to a possible rebound effect on epithelial sodium channel (ENaC) activity, a low dose of amiloride did not prevent GI262570-induced fluid retention. On the contrary, the rebound effect after amiloride treatment potentiated GI262570-induced plasma volume expansion. This is at least partially due to a synergistic effect of GI262570 and the rebound from amiloride treatment on ENaCalpha expression. In summary, our current data suggest that GI262570 can increase water and sodium reabsorption in distal nephron by stimulating the ENaC and Na,K-ATPase system. This may be an important mechanism for PPARgamma agonist-induced fluid retention.
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PMID:GI262570, a peroxisome proliferator-activated receptor {gamma} agonist, changes electrolytes and water reabsorption from the distal nephron in rats. 1547 92

To study the molecular mechanism of action of ligustrazine, a low-density oligonucleotide microarray for cardiovascular disease-related genes, was constructed, and the preparation and hybridization protocols were optimized. Under the optimized conditions, the molecular mechanism of action of ligustrazine was analyzed with human umbilical vein endothelial cells. After 4 h of treatment with 100 microg/ml of ligustrazine, calcium-ATPase gene, sodium channel gene, P450c11 gene in human umbilical vein endothelial cells were up-regulated while apolipoprotein C-III gene was down-regulated. The results were shown to be reproducible. RT-PCR confirmed the results from microarray. These results suggest that ligustrazine may act on the function of human umbilical vein endothelial cells via modulating the expressions of cardiovascular disease-related genes. This also demonstrates the use of oligonucleotide microarray technology as an approach to studying targets of active components of Traditional Chinese Medicine.
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PMID:Preparation of cardiovascular disease-related genes microarray and its application in exploring ligustrazine-induced changes in endothelial gene expression. 1552 Apr 97

Levels of oleic acid (OA) are elevated in plasma and bronchoalveolar lavage fluids of patients with acute respiratory distress syndrome (ARDS). OA is also widely used to provoke edema, by unknown mechanisms, in experimental models of ARDS. We investigated the impact of intravascularly applied OA on epithelial lining fluid balance. OA (25 microM) dramatically blocked active transepithelial (22)Na(+) transport (by 92%) in an isolated, ventilated, and perfused rabbit lung model, provoking alveolar edema, assessed by increases in lung weight and epithelial lining fluid volume. OA did not alter epithelial permeability, measured by [(3)H]mannitol and fluorescently labeled albumin flux, but did increase endothelial permeability, assessed by capillary filtration coefficient. In A549 cells, OA completely blocked amiloride-sensitive sodium currents measured by patch clamp, and also largely abrogated ouabain-sensitive Na(+),K(+)-ATPase-mediated (86)Rb(+) uptake. Although OA did not alter epithelial sodium channel or Na(+),K(+)-ATPase surface expression, it covalently associated with both molecules and directly, dramatically, and dose-dependently inhibited the catalytic activity of purified Na(+),K(+)-ATPase. Therefore, OA impaired the two essential transepithelial active sodium transport mechanisms of the lung, and could thus promote alveolar edema formation and prevent edema resolution, thereby contributing to the development of ARDS.
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PMID:Oleic acid inhibits alveolar fluid reabsorption: a role in acute respiratory distress syndrome? 1572 19

Antenatal glucocorticoids have been used for 30 years to induce maturation of preterm fetal lungs. Stimulation of the pulmonary surfactant system has been regarded as the most important effect of antenatal glucocorticoids; however, as these drugs alter the expression of a large number of genes they affect the maturation of the lung in several other ways. Antioxidant enzyme production, lung fluid absorption and alveolar development are all affected by glucocorticoids administered in the perinatal period. There is evidence that glucocorticoids induce genes associated with the synthesis of surfactant proteins, fatty acid synthase, the epithelial sodium channel and the membrane protein sodium/potassium ATPase as well as several antioxidant enzymes including catalase, glutathione peroxidase and two superoxide dismutases. Glucocorticoids also increase the expression of vascular endothelial growth factor, which may inhibit alveolarization and lead to abnormally large alveoli. The use of both antenatal and postnatal glucocorticoids has increased in the past decade. However, as concerns about possible long-term effects have arisen, the mechanisms of how glucocorticoids alter the structure and function of the lungs needs to be determined to allow the development of more specific agents in the treatment of respiratory distress syndrome.
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PMID:Effects of glucocorticoids on fetal and neonatal lung development. 1560 20

Impaired epithelial sodium channel function predisposes to delayed resorption of pulmonary edema and more severe experimental lung injury, whereas even a small fraction of the normal Na-K-ATPase activity is thought to be sufficient to maintain normal ion transport. However, direct proof is lacking. Therefore, we studied baseline and cAMP stimulated alveolar fluid clearance (AFC) in mice with a 50% decrease in lung protein expression of the alpha(1)- and/or alpha(2)-subunit of the Na-K-ATPase. There was no difference in basal and stimulated AFC in alpha(1)(+/-) or alpha(2)(+/-) mice compared with wild-type littermates. Also, the compound heterozygous mice (alpha(1)(+/-)/alpha(2)(+/-)) had normal basal AFC. However, the combined alpha(1)(+/-)/alpha(2)(+/-) mice showed a significant decrease in cAMP-stimulated AFC compared with wild-type littermates (11.1 +/- 1.0 vs. 14.9 +/- 1.8%/30 min, P < 0.001). When exposed to 96 h of >95% hyperoxia, the decrease in stimulated AFC in the alpha(1)(+/-)/alpha(2)(+/-) mice was not associated with more lung edema compared with wild-type littermates (lung wet-to-dry weight ratio 6.6 +/- 0.9 vs. 5.9 +/- 1.1, respectively; P = not significant). Thus a 50% decrease in protein expression of the alpha(1)- or alpha(2)-subunits of the Na-K-ATPase does not impair basal or stimulated AFC. However, a 50% protein reduction in both the alpha(1)- and alpha(2)-subunits of the Na-K-ATPase produces a submaximal stimulated AFC, suggesting a synergistic role for alpha(1)- and alpha(2)-subunits in cAMP-dependent alveolar epithelial fluid clearance.
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PMID:Decreased expression of both the alpha1- and alpha2-subunits of the Na-K-ATPase reduces maximal alveolar epithelial fluid clearance. 1578 23


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