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)

Potassium depletion is involved in the pathophysiology of metabolic alkalosis. In the present study, the expression of renal acid-base transporters that are involved in HCO3- reabsorption was studied in potassium depletion. Rats fed potassium-deficient (KD) diet developed significant hypokalemia at 14 days (serum K+ 1.9 +/- 0.2 in KD vs. 4.2 +/- 0.2 meq/l in control, P < 0.01) but not at 6 days (3.8 +/- 0.3 in KD vs. 4.1 +/- 0.3 meq/l in control, P > 0.05). Kidney mRNA for colonic H(+)-K(+)-adenosinetriphosphatase (H(+)-K(+)-ATPase, cHKA) increased by approximately 3- and 11-fold at 6 and 14 days of KD diet, respectively, indicating that increased expression preceded the onset of hypokalemia. The expression of Na+/H+ exchanger 3 (NHE-3) mRNA and its cognate protein remained unchanged at 6 and 14 days of KD diet. The mRNA levels for NHE-1, NHE-2, and NHE-4 also remained unchanged at 6 and 14 days of KD diet. Hypophysectomized (HPX) rats fed KD diet for 14 days developed similar hypokalemia. However, the expression of cHKA mRNA in the kidney was decreased by approximately 80% in potassium-depleted (HPX+KD) rats (P < 0.01 vs. KD only). Hypophysectomy did not affect the mRNA levels for either gastric H(+)-K(+)-ATPase (gHKA) or NHE isoforms in KD animals. Thus potassium depletion increases expression of cHKA in the kidney but not that of gHKA or NHE isoforms. The signal for this increase appears to precede hypokalemia. Furthermore, the data suggest that pituitary hormone(s) plays an important and novel role in the regulation of cHKA.
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PMID:Potassium depletion and acid-base transporters in rat kidney: differential effect of hypophysectomy. 922 34

The H+ and HCO3- transporters present in the medullary thick ascending limb (MTAL) of the kidney are involved in several functions, such as transepithelial transport, defense of cell pH and cell volume. Apical H+ secretion occurs via the NHE-3 and NHE-2 isoforms of the Na+/H+ exchanger, and H(+)-ATPase. The apical Na+/H+ exchanger is responsible for most of the apical step of transepithelial HCO3- absorption and is unresponsive to cell acidification under isosmotic conditions. Basolateral HCO3- efflux mechanisms may occur via the Cl-/HCO3- exchanger and via the cotransporters K+/HCO3- (in the rat) and Na-3HCO3- (in the mouse). However, the role of each transporter in transepithelial HCO3- absorption is currently unknown. Inhibition of the basolateral Na+/H+ exchanger (NHE-1) paradoxically inhibits the apical Na+/H+ exchanger. This cross talk is independent of cell pH and may involve variations in cell volume. Arginine vasopressin (AVP) and hyperosmolality induce a differential regulation of basolateral NHE-1 and the apical Na+/H+ exchanger. They stimulate the basolateral NHE-1, and the resulting cell alkalinization probably stimulates the pHi-sensitive AE2, which restores cell volume by cellular uptake of NaCl. They also inhibit the apical Na+/H+ exchanger, which reduces net HCO3- absorption and thus may prevent interstitial fluid alkalinization. Chronic metabolic acidosis markedly increases HCO3- absorptive capacity of MTAL, by stimulating at least the synthesis of apical NHE-3 protein, as in the proximal tubule. Conversely, chronic metabolic alkalosis reduces the apical NHE-3 transport activity by decreasing the synthesis of NHE-3 protein. The paradoxical increase in HCO3- absorptive capacity of MTAL observed in the model of chronic NaHCO3-load alkalosis should be due to other factors overcoming the inhibitory effect of alkalosis on NHE-3.
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PMID:H+ and HCO3- transporters in the medullary thick ascending limb of the kidney: molecular mechanisms, function and regulation. 955 30

Both Na+/H+ exchange and the electrogenic extrusion of H+ via an H+-ATPase have been postulated to drive acid excretion across the branchial epithelium of fishes. While the H+-ATPase/Na+ channel system appears to be the predominant mechanism in some freshwater species, it may play a reduced role in seawater and brackish-water animals, where high external Na+ concentrations may thermodynamically favor Na+/H+ exchange driven by a Na+/H+ antiporter (NHE). In this study, we used molecular and immunological methods to assess the role of NHE isoforms in the branchial epithelium of the marine long-horned sculpin (Myoxocephalus octodecimspinosus) and the euryhaline killifish (Fundulus heteroclitus). Northern blot analysis of RNA probed with the human NHE-1 BamHI fragment suggested the presence of homologous gill NHE mRNA in sculpin. RT-PCR on gill RNA isolated from sculpin recovering from metabolic acidosis provided evidence for two distinct NHE isoforms; one with 76 % amino acid homology to mammalian NHE-2, and another 92 % homologous to trout erythrocytic beta-NHE. Killifish also have transcripts with 91 % homology to beta-NHE. Immunological detection using monoclonal antibodies for mammalian NHE-1 revealed a protein antigenically similar to this isoform in the gills of both species. Metabolic acidosis caused an approximately 30-fold decrease in expression of the NHE-1-like protein in sculpin. We speculate that beta-NHE in the gills plays the intracellular 'housekeeping' roles described for mammalian NHE-1. During systemic acidosis, apical gill NHE-2 (which is sensitive to external amiloride and low [Na+]) in parallel with a dramatic suppression of basolateral NHE-1 activity enhances net capdelta H+ transfers to the water.
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PMID:A mechanism for branchial acid excretion in marine fish: identification of multiple Na+/H+ antiporter (NHE) isoforms in gills of two seawater teleosts. 988 43

NHE3 is the predominant isoform responsible for apical membrane Na(+)/H(+) exchange in the proximal tubule. Deletion of NHE3 by gene targeting results in an NHE3(-/-) mouse with greatly reduced proximal tubule HCO(-)(3) absorption compared with NHE3(+/+) animals (P. J. Schultheis, L. L. Clarke, P. Meneton, M. L. Miller, M. Soleimani, L. R. Gawenis, T. M. Riddle, J. J. Duffy, T. Doetschman, T. Wang, G. Giebisch, P. S. Aronson, J. N. Lorenz, and G. E. Shull. Nature Genet. 19: 282-285, 1998). The purpose of the present study was to evaluate the role of other acidification mechanisms in mediating the remaining component of proximal tubule HCO(-)(3) reabsorption in NHE3(-/-) mice. Proximal tubule transport was studied by in situ microperfusion. Net rates of HCO(-)(3) (J(HCO3)) and fluid absorption (J(v)) were reduced by 54 and 63%, respectively, in NHE3 null mice compared with controls. Addition of 100 microM ethylisopropylamiloride (EIPA) to the luminal perfusate caused significant inhibition of J(HCO3) and J(v) in NHE3(+/+) mice but failed to inhibit J(HCO3) or J(v) in NHE3(-/-) mice, indicating lack of activity of NHE2 or other EIPA-sensitive NHE isoforms in the null mice. Addition of 1 microM bafilomycin caused a similar absolute decrement in J(HCO3) in wild-type and NHE3 null mice, indicating equivalent rates of HCO(-)(3) absorption mediated by H(+)-ATPase. Addition of 10 microM Sch-28080 did not reduce J(HCO3) in either wild-type or NHE3 null mice, indicating lack of detectable H(+)-K(+)-ATPase activity in the proximal tubule. We conclude that, in the absence of NHE3, neither NHE2 nor any other EIPA-sensitive NHE isoform contributes to mediating HCO(-)(3) reabsorption in the proximal tubule. A significant component of HCO(-)(3) reabsorption in the proximal tubule is mediated by bafilomycin-sensitive H(+)-ATPase, but its activity is not significantly upregulated in NHE3 null mice.
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PMID:Mechanism of proximal tubule bicarbonate absorption in NHE3 null mice. 1044 85

The branchial epithelium of the mudskipper Periophthalmodon schlosseri is densely packed with mitochondria-rich (MR) cells. This species of mudskipper is also able to eliminate ammonia against large inward gradients and to tolerate extremely high environmental ammonia concentrations. To test whether these branchial MR cells are the sites of active ammonia elimination, we used an immunological approach to localize ion-transport proteins that have been shown pharmacologically to be involved in the elimination of NH(4)(+) (Na(+)/NH(4)(+) exchanger and Na(+)/NH(4)(+)-ATPase). We also investigated the role of carbonic anhydrase and boundary-layer pH effects in ammonia elimination by using the carbonic anhydrase inhibitor acetazolamide and by buffering the bath water with Hepes, respectively. In the branchial epithelium, Na(+)/H(+) exchangers (both NHE2- and NHE3-like isoforms), a cystic fibrosis transmembrane regulator (CFTR)-like anion channel, a vacuolar-type H(+)-ATPase (V-ATPase) and carbonic anhydrase immunoreactivity are associated with the apical crypt region of MR cells. Associated with the MR cell basolateral membrane and tubular system are the Na(+)/K(+)-ATPase and a Na(+)/K(+)/2Cl(-) cotransporter. A proportion of the ammonia eliminated by P. schlosseri involves carbonic anhydrase activity and is not dependent on boundary-layer pH effects. The apical CFTR-like anion channel may be serving as a HCO(3)(-) channel accounting for the acid-base neutral effects observed with net ammonia efflux inhibition.
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PMID:Immunolocalization of ion-transport proteins to branchial epithelium mitochondria-rich cells in the mudskipper (Periophthalmodon schlosseri). 1088 68

An acidic luminal pH in the epididymis and vas deferens (VD) helps maintain mature sperm in an immotile state during storage. We have previously shown that the majority of proton secretion in the VD is due to the activity of the vacuolar H+-ATPase. Acidification is dependent on luminal sodium in more proximal regions of the epididymis, and we examined the distribution of the Na+/H+ exchanger, NHE3, by immunofluorescence and measured Na+/H+ exchange (NHE) activity in isolated epididymal tubules. NHE3 was detected in the apical pole of nonciliated cells of the efferent ducts and principal cells (PC) of the epididymis. No staining was seen in the distal cauda epididymidis and the VD. Isolated tubules from the distal initial segment (DIS) and proximal cauda epididymidis were perfused in vitro and loaded with the pH-sensitive dye 2',7'-bis(carboxyethyl)-5(6')-carboxyfluorescein. Ethylisopropyl amiloride (EIPA) (50 microM) reduced the initial rate of intracellular pH recovery (dpH(i)/dt), in response to an acute acid load, by 51% and 45% in the DIS and cauda epididymidis, respectively. In the DIS, removal of luminal sodium reduced dpH(i)/dt by 52%. HOE694 (50 microM) inhibited all EIPA-sensitive dpH(i)/dt in the DIS, despite the previously reported absence of NHE2 in this region (Cheng Chew SB, Leung GPH, Leung PY, Tse CM, and Wong PYD, Biol Reprod 62: 755-758, 2000). These data indicate that HOE694- and EIPA-sensitive Na+/H+ exchange may participate, together with the H+-ATPase, in luminal acidification in the male excurrent duct.
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PMID:Na+/H+-exchange activity and immunolocalization of NHE3 in rat epididymis. 1118 4

It is well recognized that ileostomy patients suffer from chronic depletion of Na(+) through the stoma effluent. In this study we evaluated the effects of ileostomy on messenger RNA levels that encode different Na(+)/H(+) exchanger isoforms (NHE-2 and NHE-3). Loop ileostomies were created in Sprague-Dawley rats. Segments of diverted ileum were harvested for quantitation of mRNA levels encoding these isoforms and the Na(+)/K(+) ATPase in mucosal scrapings and for immunofluorescence microscopy, specifically of the NHE-3 protein. Our studies indicate that as early as 8 days after diversion, NHE-3 gene expression is selectively attenuated in poststomal ileal mucosa. Mucosal morphology remains undisturbed, and the distribution of protein expression along the crypt/villus axis is not altered. Infusion of Na(+) or the enterocyte nutrient, glutamine, into the lumen of the diverted segment restores or even augments mRNA levels for NHE-3, again without altering the histologic appearance or distribution of the protein along the crypt/villus axis. These effects are specific because nonpolar osmolytes (mannitol) and related organic nutrients not specific for the enterocyte (i.e., butyrate) have no effect on mRNA levels of NHE-3. Further work is required to understand how the early changes in mRNA contribute to mucosal function and response to luminal diversion.
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PMID:Luminal regulation of Na(+)/H(+) exchanger gene expression in rat ileal mucosa. 1202 91

The mechanisms underlying acid-base transfers across the branchial epithelium of fishes have been studied for more than 70 years. These animals are able to compensate for changes to internal pH following a wide range of acid-base challenges, and the gill epithelium is the primary site of acid-base transfers to the water. This paper reviews recent molecular, immunohistochemical, and functional studies that have begun to define the protein transporters involved in the acid-base relevant ion transfers. Both Na(+)/H(+) exchange (NHE) and vacuolar-type H(+)-ATPase transport H(+) from the fish to the environment. While NHEs have been thought to carry out this function mainly in seawater-adapted animals, these proteins have now been localized to mitochondrial-rich cells in the gill epithelium of both fresh and saltwater-adapted fishes. NHEs have been found in the gill epithelium of elasmobranchs, teleosts, and an agnathan. In several species, apical isoforms (NHE2 and NHE3) appear to be up-regulated following acidosis. In freshwater teleosts, H(+)-ATPase drives H(+) excretion and is indirectly coupled to Na(+) uptake (via Na(+) channels). It has been localized to respiratory pavement cells and chloride cells of the gill epithelium. In the marine elasmobranch, both branchial NHE and H(+)-ATPase have been identified, suggesting that a combination of these mechanisms may be utilized by marine elasmobranchs for acid-base regulation. An apically located Cl(-)/HCO(3)(-) anion exchanger in chloride cells may be responsible for base excretion in fresh and seawater-adapted fishes. While only a few species have been examined to date, new molecular approaches applied to a wider range of fishes will continue to improve our understanding of the roles of the various gill membrane transport processes in acid-base balance.
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PMID:Acid-base regulation in fishes: cellular and molecular mechanisms. 1211 3

Short-term exposure of coho salmon smolts (Oncorhynchus kisutch) to a gradual increase in salinity over 2 d (0 per thousand -32 per thousand ) resulted in a decrease in proton pump abundance, detected as changes in immunoreactivity with a polyclonal antibody against subunit A of bovine brain vacuolar H(+)-ATPase. N-ethylmaleimide (NEM)-sensitive H(+)-ATPase activities in gill homogenates remained unchanged over 8 d to coincide with a 3.5-fold increase in Na(+)/K(+)-ATPase activities. A transient increase in plasma [Na(+)] and [Cl(-)] levels over the 8-d period was preceded by a 10-fold increase in plasma cortisol levels, which peaked after 12 h. Long-term (1 mo) acclimation to seawater resulted in the loss of apical immunoreactivity for vH(+)-ATPase and band 3-like anion exchanger in the mitochondria-rich cells identified by high levels of Na(+)/K(+)-ATPase immunoreactivity. The polyclonal antibody Ab597 recognized a Na(+)/H(+) exchanger (NHE-2)-like protein in what appears to be an accessory cell (AC) type. Populations of these ACs were found associated with Na(+)/K(+)-ATPase rich chloride cells in both freshwater- and seawater-acclimated animals.
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PMID:Ionoregulatory changes in the gill epithelia of coho salmon during seawater acclimation. 1217 27

Until recently, it was not feasible to conduct genome-wide screening for gene transcript variations that play key roles in the pathogenesis of otitis media. In this study microarray technology was used to profile differential gene expression patterns from rat middle ear mucosa at 12 and 48 h after Streptococcus pneumoniae challenge. Real-time polymerase chain reaction was performed for independent verification of the microarray results. Three ion transport mRNAs were simultaneously suppressed more than 4-fold at 12 h in bacteria-challenged ears, including Na,K-ATPase alpha I subunit (SPATPa1), sodium channel beta 2 subunit (SCNB2) and sodium-hydrogen exchange protein isoform 2 subunit (NHE2). At 48 h after infection, the mRNA levels of SCNB2 and NHE2 had decreased 7- and 10-fold, respectively, whereas the relatively abundant SPATPa1 transcript showed recovery. The downregulation of Na(+)-transporting transcripts suggests a reduced number of epithelial cells and transporting proteins and/or the dysfunction of sodium transporters secondary to the bacterial infection. These changes can disrupt the coupling of the apical Na + entry and basolateral Na + extrusion, deplete the electrochemical Na+ transmembrane gradient, disrupt the intracellular osmotic equilibrium and lead to intracellular acidification and the accumulation of excess sodium, water and other organic and inorganic molecules in the middle ear cavity. Any or all of these changes may contribute to the initiation and persistence of middle ear mucosa inflammation and effusion during an episode of bacterial acute otitis media.
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PMID:Suppression of epithelial ion transport transcripts during pneumococcal acute otitis media in the rat. 1220 56


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