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 mineralocorticoid hormone aldosterone stimulates transcellular Na+ reabsorption across target epithelia after a lag period of 20 to 60 min by first activating preexisting channels (epithelial sodium channels, ENaC) and pumps (Na-K-ATPase) and, subsequently, increasing the overall transport capacity of the cells. Both these early regulatory and late anabolic-type actions depend on the transcriptional regulation exerted by hormone-activated mineralocorticoid and/or glucocorticoid receptors (MR and/or GR). Starting at the transcriptional side of the aldosterone action, recent studies have identified the small G protein K-Ras2 and the kinase sgk as the first early aldosterone-induced gene products potentially regulating Na+ transport. At the level of the Na+ transport effectors, much knowledge about ENaC and Na-K-ATPase structure-function relationship and regulation has accumulated. However, the regulatory pathway(s) that link the transcriptional action of aldosterone to these Na+ transport proteins is still to a large extent unknown. The available data suggest that the early regulatory action of aldosterone is pleiotropic, similarly to the late anabolic-type action. The early Na+ transport stimulation would be mediated by the rapid induction of gene products belonging to the regulatory network that integrates the inputs of diverse pathways and finally controls the function of the Na+ transport machinery.
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PMID:Early aldosterone action: toward filling the gap between transcription and transport. 1048 14

Aldosterone increases within 30 min renal Na+reabsorption and K+secretion by a mechanism that is triggered at the level of gene transcription. Thus, gene products that are rapidly up- or down-regulated transmit this effect to the transport machinery within the distal nephron target cells. One such rapidly up-regulated gene product is a structural element of the transport machinery, namely the a subunit of ENaC. Its amount might in certain conditions play a rate limiting role for Na+transport. Cell-surface localization and function of ENaC and of the Na,K-ATPase are also tightly controlled by a complex regulatory network and aldosterone appears to acutely regulate the expression of elements of this network such as the small G-protein K-Ras (in A6 cells) and the kinase SGK1 (also in ENaC-expressing cells of the mammalian distal nephron). The kinase SGK1 is an early aldosterone-induced protein that relays signals from pathways that are transmitted via PDK1/2 and possibly PKA. Active SGK1 has been shown to increase ENaC and Na,K-ATPase cell-surface expression in Xenopus oocytes. This effect at the level of ENaC has been recently shown to be mediated by the ubiquitin ligase Nedd4-2 which is a direct target of SGK1. Once phosphorylated by SGK1, Nedd4-2 is prevented from interacting with ENaC and thus from decreasing ENaC cell-surface expression. This SGK1-Nedd4-2-ENaC pathway is the first direct link between aldosterone-induced transcriptional regulation and the function of the Na+transport machinery to be unravelled. The physiological importance of this pathway for mediating the aldosterone response in different target epithelia remains to be verified in vivo, in particular in view of the axial gradient of ENaC apical translocation observed along the aldosterone-sensitive distal nephron.
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PMID:SGK1: aldosterone-induced relay of Na+ transport regulation in distal kidney nephron cells. 1264 99

Aldosterone controls extracellular volume and blood pressure by regulating Na(+) reabsorption across epithelial cells of the aldosterone-sensitive distal nephron (ASDN). This effect is mediated by a coordinate action on the luminal channel ENaC (generally rate limiting) and the basolateral Na,K-ATPase. Long-term effects of aldosterone (starting within 3 to 6 hours and increasing over days) are mediated by the direct and indirect induction of stable elements of the Na(+) transport machinery (e.g., Na,K-ATPase alpha subunit), whereas short-term effects appear to be mediated by the upregulation of short-lived elements of the machinery (e.g., ENaC alpha subunit) and of regulatory proteins, such as the serum- and glucocorticoid-regulated kinase SGK1. We have recently shown that in cortical collecting duct (CCD) from adrenalectomized (ADX) rats, the increase in Na,K-ATPase activity (approximately threefold in 3 h), induced by a single aldosterone injection, can be fully accounted for by the increase in Na,K-ATPase cell-surface expression. Using the model cell line mpkCCD(cl4), we showed that the parallel increase in Na,K-ATPase function [assessed by Na(+) pump current (I(p)) measurements] and cell-surface expression depends on transcription and translation, and that it is not secondary to a change in apical Na(+) influx. As a first approach to address the question whether the aldosterone-induced regulatory protein SGK1 might play a role in mediating Na,K-ATPase translocation, we have used the Xenopus laevis expression system. SGK1 coexpression indeed increased both the Na(+) pump current and the surface expression of pumps containing the rat alpha1 subunits. In summary, aldosterone controls Na(+) reabsorption in the short term not only by regulating the apical cell-surface expression of ENaC but also by coordinately acting on the basolateral cell-surface expression of the Na,K-ATPase. Results obtained in the Xenopus oocyte expression system suggest the possibility that this effect could be mediated in part by the aldosterone-induced kinase SGK1.
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PMID:Short-term aldosterone action on Na,K-ATPase surface expression: role of aldosterone-induced SGK1? 1276 89

Changes in adrenal corticosteroid secretion result in changes in lung liquid production in the late-gestation fetus. To test for the presence of mineralocorticoid receptor (MR) in fetal pulmonary epithelium, lungs from fetal sheep of 120 to 130 days' gestation (term about 148 days) were collected and frozen for identification of mRNA for MR in homogenates by reverse transcriptase polymerase chain reaction (RT-PCR) or for determination of 3H-cortisol binding at MR. Other samples of fetal lungs were fixed for localization of MR and Na+, K+ adenosine triphosphatase (ATPase) alpha by immunohistochemistry. MR mRNA was identified in lung tissue from fetuses and newborn lambs, but not from pregnant ewes; MR-regulated genes, including SGK1 and ENaCalpha were also expressed in fetal and newborn lungs. Immunoreactive MR was found in pulmonary epithelial cells and to be colocalized with Na+, K+ ATPase alpha in many sites. These results indicate that the molecular apparatus for mineralocorticoid-stimulated lung liquid reabsorption is present in epithelium by 120 days' gestation.
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PMID:Mineralocorticoid receptor expression in late-gestation ovine fetal lung. 1569 2

Glucocorticoids blunt insulin release, an effect partially due to activation of Kv channels. Similar to those channels Na+/K+ ATPase activity repolarizes the plasma membrane. The present study explored whether glucocorticoids increase the Na+/K+ ATPase activity in pancreatic beta-cells. The glucocorticoid dexamethasone (100 nmol/l for 1 day) significantly increased Na+/K+ ATPase alpha1/beta1-subunit transcript levels and ouabain-sensitive outward current reflecting Na+/K+ ATPase activity in INS-1 cells, effects blunted by glucocorticoid-receptor-blocker RU487 (1 micromol/l). Dexamethasone (100 nmol/l) increased K+ current in beta-cells from wild type mice but not from knockout mice lacking functional serum and glucocorticoid inducible kinase SGK1. Thus, glucocorticoids indeed up-regulate Na+/K+ ATPase activity, an effect requiring SGK1.
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PMID:Dexamethasone increases Na+/K+ ATPase activity in insulin secreting cells through SGK1. 1715 65

Glucocorticoids stimulate gastric acid secretion, an effect favoring the development of peptic ulcers. Putative mechanisms involved include the serum- and glucocorticoid-inducible kinase (SGK1), which stimulates a variety of epithelial channels and transporters. The present study explored the contribution of SGK1 to effects of glucocorticoids on gastric acid secretion. In isolated gastric glands from gene-targeted mice lacking functional SGK1 (sgk1 (-/-)) and their wild-type littermates (sgk1 (+/+)), H(+)-secretion (DeltapH/min) was determined utilizing 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF)-fluorescence, SGK1 transcript levels by in situ hybdridization, and expression of KCNQ1 channels by immunohistochemistry and real-time polymerase chain reaction. SGK1 transcript levels were enhanced by a 4-day treatment with 10 mug/g body weight (BW)/day dexamethasone (DEX). Before treatment, DeltapH/min was similar in sgk1 (-/-) and sgk1 (+/+)mice. DEX increased DeltapH/min approximately fourfold in sgk1 (+/+)mice and approximately twofold in sgk1 (-/-)mice, effects abolished in the presence of K(+)/H(+)ATPase-inhibitor omeprazole (50 microM). Increase in local K(+) concentrations to 35 mM (replacing Na(+)) enhanced DeltapH/min, which could not be further stimulated by DEX and was not significantly different between sgk1 (-/-) and sgk1 (+/+)mice. Carbachol (100 microM) and forskolin (5 microM) stimulated gastric acid secretion to a similar extent in sgk1 (-/-) and sgk1 (+/+)mice. In conclusion, SGK1 is not required for basal and cyclic AMP-stimulated gastric H(+) secretion but participates in the stimulation of gastric H(+) secretion by glucocorticoids. The effects of glucocorticoids and SGK1 are not additive to an increase in extracellular K(+) concentration and may thus involve stimulation of K(+) channels.
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PMID:Role of the serum and glucocorticoid inducible kinase SGK1 in glucocorticoid stimulation of gastric acid secretion. 1761 52

Insulin stimulates cellular K+ uptake leading to hypokalemia. Cellular K+ uptake is accomplished by parallel stimulation of Na+/H+ exchange, Na+,K+,2Cl- co-transport, and Na+/K+ ATPase and leads to cell swelling, a prerequisite for several metabolic effects of the hormone. Little is known about underlying signaling. Insulin is known to activate the serum and glucocorticoid-inducible kinase SGK1, which in turn enhances the activity of all three transport proteins. The present study thus explored the contribution of SGK1 to insulin-induced hypokalemia. To this end, gene-targeted mice lacking SGK1 (sgk1-/-) and their wild-type littermates (sgk1+/+) have been infused with insulin (2 mU kg(-1) min(-1)) and glucose at rates leaving the plasma glucose concentration constant. Moreover, isolated liver perfusion experiments have been performed to determine stimulation of cellular K+ uptake by insulin (100 nM). As a result, combined glucose and insulin infusion significantly decreased plasma K+ concentration despite a significant decrease of urinary K+ excretion in sgk1+/+ but not in sgk1-/- mice. Accordingly, the plasma K+ concentration was within 60 min significantly lower in sgk1+/+ than in sgk1-/- mice. In isolated liver perfusion experiments, cellular K+ uptake was stimulated by insulin (100 nM), an effect blunted by 72% in sgk1-/- mice as compared to sgk1+/+ mice. Accordingly, insulin-induced cell hydration was 63% lower in sgk1-/- mice than in sgk1+/+ mice. Moreover, volume regulatory K+ release was 31% smaller in sgk1-/- mice than in sgk1+/+ mice. In conclusion, the serum and glucocorticoid-inducible kinase SGK1 participates in the signaling mediating the hypokalemic effect of insulin.
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PMID:SGK1 dependence of insulin induced hypokalemia. 1866 90

Reissner's membrane epithelium forms much of the barrier that produces and sustains the large ionic differences between cochlear endolymph and perilymph. We have reported that Reissner's membrane contributes to normal cochlear function by absorbing Na(+) from endolymph via amiloride-sensitive channels in gerbil inner ear. We used mouse Reissner's membrane to 1) identify candidate genes involved in the Na(+) transport pathway, 2) determine whether their level of expression was regulated by the synthetic glucocorticoid dexamethasone, and 3) obtain functional evidence for the physiological importance of these genes. Transcripts were present for alpha-, beta-, and gamma-subunits of epithelial Na(+) channel (ENaC); corticosteroid receptors GR (glucocorticoid receptor) and MR (mineralocorticoid receptor); GR agonist regulator 11beta-hydroxysteroid dehydrogenase (HSD) type 1 (11beta-HSD1); Na(+) transport control components SGK1, Nedd4-2, and WNKs; and K(+) channels and Na(+)-K(+)-ATPase. Expression of the MR agonist regulator 11beta-HSD2 was not detected. Dexamethasone upregulated transcripts for alpha- and beta-subunits of ENaC ( approximately 6- and approximately 3-fold), KCNK1 ( approximately 3-fold), 11beta-HSD1 ( approximately 2-fold), SGK1 ( approximately 2-fold), and WNK4 ( approximately 3-fold). Transepithelial currents from the apical to the basolateral side of Reissner's membrane were sensitive to amiloride (IC(50) approximately 0.7 muM) and benzamil (IC(50) approximately 0.1 muM), but not EIPA (IC(50) approximately 34 muM); amiloride-blocked transepithelial current was not immediately changed by forskolin/IBMX. Currents were reduced by ouabain, lowered bath Na(+) concentration (from 150 to 120 mM), and K(+) channel blockers (XE-991, Ba(2+), and acidification from pH 7.4 to 6.5). Dexamethasone-stimulated current and gene expression were reduced by mifepristone, but not spironolactone. These molecular, pharmacological, and functional observations are consistent with Na(+) absorption by mouse Reissner's membrane, which is mediated by apical ENaC and/or other amiloride-sensitive channels, basolateral Na(+)-K(+)-ATPase, and K(+)-permeable channels and is under the control of glucocorticoids. These results provide an understanding and a molecular definition of an important transport function of Reissner's membrane epithelium in the homeostasis of cochlear endolymph.
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PMID:Regulation of ENaC-mediated sodium transport by glucocorticoids in Reissner's membrane epithelium. 1914 62

Adenomatous polyposis coli (APC) is a tumor suppressor gene inactivated in familial adenomatous polyposis and sporadic colorectal cancer. Mice carrying a loss-of-function mutation in the apc gene (apc(Min/+)) spontaneously develop gastrointestinal tumors. APC fosters degradation of beta-catenin, which in turn upregulates the serum- and glucocorticoid-inducible kinase SGK1. SGK1 stimulates KCNQ1, which is required for luminal K+ recycling and thus for gastric acid secretion. BCECF-fluorescence was utilized to determine gastric acid secretion in isolated gastric glands from apc(Min/+) mice and their wild type littermates (apc(+/+)). Western blotting was employed to analyse beta-catenin and SGK1 expression and immunohistochemistry to determine KCNQ1 protein abundance. beta-catenin and SGK1 expression were enhanced in apc(Min/+) mice. Cytosolic pH was similar in apc(Min/+) mice and apc(+/+) mice. Na+-independent pH recovery following an ammonium pulse (DeltapH/min), which reflects H+/K+ ATPase activity, was, however, significantly faster in apc(Min/+) mice than in apc(+/+)mice. In both genotypes DeltapH/min was abolished in the presence of H+/K+ ATPase inhibitor omeprazole (100 microM). Treatment of apc(Min/+) and apc(+/+)mice with 5 microM forskolin 15 minutes prior to the experiment or increase in local K+-concentrations to 35 mM (replacing Na+/NMDG) significantly increased DeltapH/min and abrogated the differences between genotypes. The increase of DeltapH/min in apc(Min/+)mice required SGK1, as it was abolished by additional knockout of SGK1 (apc(Min/+)/sgk1(-/-)). In conclusion, basal gastric acid secretion is significantly enhanced in apc(Min/+)mice, pointing to a role of APC in the regulation of gastric acid secretion. The effect of APC requires H+/K+ ATPase activity and is at least partially due to SGK1-dependent upregulation of KCNQ1.
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PMID:APC sensitive gastric acid secretion. 1925 8

Androgen receptor (AR) plays a pivotal role in prostate cancer, primarily by regulating different gene expression programs elicited by androgen, which is important for cancer cell proliferation, survival, and differentiation. It is believed that the transcriptional function of AR is mediated largely by distinct nuclear coregulators. We report here the identification of ANCCA (also known as ATAD2), a new member of the AAA+ ATPase family proteins, as a novel AR coactivator. ANCCA interacts directly with AR and enhances its transcriptional activity, and is required for androgen-stimulated expression of a specific subgroup of genes including IGF1R, IRS-2, SGK1, and survivin. Upon androgen stimulation, ANCCA together with AR is recruited to the specific AR target genes. Suppression of ANCCA expression strongly inhibited the proliferation of androgen-responsive or androgen-independent, AR-positive prostate cancer cells and caused a significant increase of cellular apoptosis. Strikingly, the ANCCA gene itself, located at chromosome 8q24, is highly induced by androgen in androgen-dependent prostate cancer cells and xenograft tumors. Although ANCCA is hardly detected in normal human prostate tissue, high levels of ANCCA are found in hormone-independent prostate cancer cell lines, xenograft tumor, and a subset of prostate cancers with high Gleason scores. Together, these findings suggest that ANCCA plays an important role in prostate cancer by mediating specific AR functions in cancer cell survival and proliferation. The possession of ATPase and bromodomain by ANCCA makes it an attractive target for the development of therapeutics for the disease.
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PMID:Androgen-induced coactivator ANCCA mediates specific androgen receptor signaling in prostate cancer. 1931 66


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