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)

Abnormal growth of vascular smooth muscle (VSM) is seen in various pathologic conditions such as hypertension and atherosclerosis. Many classic vasoconstrictors have now been shown to be mitogenic, either by themselves or in conjunction with other cofactors, such as insulin. The mitogenic effects of vasoconstrictors may be due, in part, to activation of similar second messenger pathways, including stimulation of the Na+/H+ antiporter. It has been suggested, therefore, that an enhanced proliferation rate may be, in part, the consequence of elevated Na+/H+ exchange. This hypothesis is supported by several observations of the close association between Na+/H+ exchange activity and DNA synthesis in some cell types including fibroblasts and VSM. Stimulation of Na+/H+ exchange may play a permissive role in optimal growth by preventing H+ accumulation (a fall in intracellular pH [pHi]) due to the increased metabolic activity during cell stimulation. Enhancement of Na+/H+ exchange activity increases Na+ influx into the cell, and secondarily increases K+ entry through activation of Na+/K+ ATPase activity. Although the Na+/H+ antiporter may influence cell proliferation through various ionic mechanisms, it is not clear that enhanced proliferation is the consequence of overactivity of this antiporter. In VSM, there are also differences in the pattern of activation of the Na+/H+ antiporter by hyperplastic and hypertrophic agents. Although pHi is increased in response to both acute and chronic stimulation by hyperplastic factors, such as platelet-derived growth factor, a hypertrophic agonist such as angiotensin II increases pHi acutely but lowers it chronically. Likewise, hyperplastic factors increase the Na+/H+ antiporter (NHE-1) mRNA levels, whereas angiotensin II does not.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Na+/H+ exchange and vascular smooth muscle proliferation. 814 Nov 73

The gastric mucosa secretes both protons and bicarbonate. The molecular identity of the H(+)-K(+)-ATPase, which mediates acid secretion, has long been known, but the other components of the secretory machinery and their cellular disposition are less well characterized. This study identifies and localizes in rat and rabbit gastric mucosa a chloride-bicarbonate exchanger protein and a Na(+)-H+ exchanger protein. The previously described band 3-related protein of the parietal cell has been identified by isoform-specific antibodies as anion exchanger (AE) 2 and localized to the basolateral membranes of the parietal cells. The Na(+)-H+ exchanger protein NHE-1 was located in the basolateral membranes of the mucous neck cells, interdigitated between the parietal cells of the gastric glands and in the basolateral membranes of the surface mucous cells. Neither transporter protein was abundantly expressed deep in the gland, where most of the pepsinogen cells reside. Carbonic anhydrase II (CA II) was expressed at higher abundance in the surface mucous cells and mucous neck cells, which expressed NHE-1, than in the parietal cells, which expressed AE2. The morphological evidence identified AE2 as a major parietal cell anion exchanger, whereas NHE-1 and CA II colocalized in mucous neck, chief, and surface mucous cells. We propose that all three of these cell types contribute to gastric bicarbonate secretion.
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PMID:Immunolocalization of anion exchanger AE2 and cation exchanger NHE-1 in distinct adjacent cells of gastric mucosa. 814 Dec 71

It has been suggested that Ca2+ transients, acting through calmodulin-binding proteins, play a role in the activation of the Na+/H+ exchanger isoform NHE1 (Owen and Villereal, 1982a, Biochem. Biophys. Res. Commun., 109:762-768; 1982b, Proc. Natl. Acad. Sci. U.S.A., 79:3537-3541, Ober and Pardee, 1987, J. Cell. Physiol., 132:311-317). This is supported by a recent report that NHE1 is a calmodulin-binding protein and that loss of the high-affinity calmodulin-binding site results in alterations in antiporter function (Bertrand, et al., 1994, J. Biol. Chem., 269:13703-13709). An additional mechanism by which NHE1 is activated by mitogens is thought to be phosphorylation (Sardet, et al., 1990, Science 247:723-726). Although the calmodulin-binding region appears vital to antiporter activation, the role of phosphorylation is unclear. The studies presented here examine a role for Ca2+ in the activation and phosphorylation of NHE1 induced by serum and hypertonicity. It is apparent that the microsomal Ca2+ ATPase inhibitor thapsigargin activates antiporter function in human foreskin fibroblasts (HSWP) as determined by increased intracellular alkalinization examined by image analysis. This effect is Ca(2+)-dependent as the alkalinization is blocked when cells are preincubated with BAPTA, an intracellular Ca2+ chelator. Similarly, the effects of serum-induced intracellular alkalinization are inhibited by BAPTA. In contrast, activation of NHE1 by increased osmolarity was not inhibited by BAPTA. This suggests that serum, and not hypertonicity, increases intracellular pH via a Ca(2+)-dependent process. It was also observed that both thapsigargin and hypertonicity activate NHE1 by a phosphorylation-independent mechanism and that BAPTA did not block the serum-induced increase in phosphorylation of NHE1. These results indicate that Ca2+ plays the predominant role in the serum-induced activation of NHE1, while phosphorylation plays only a minor, if any, role in this process. However, Ca2+ does not appear to be involved in the osmotic regulation of NHE1.
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PMID:Examination of the role for Ca2+ in regulation and phosphorylation of the Na+/H+ antiporter NHE1 via mitogen and hypertonic stimulation. 864 25

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

To characterize and localize a K+/H+ antiport mechanism in the renal medullary thick ascending limb (MTAL), membrane vesicles were isolated from a rat MTAL homogenate. K+/H+ antiport (in > out H+ gradient-stimulated 86Rb+ uptake) was abolished by barium and verapamil (apparent Ki of 55 microM) but unaffected by other K+ channel blockers such as quinidine and high amiloride concentrations. SCH 28080, a H+/K+-ATPase blocker, did not affect K+/H+ antiport. K+/H+ antiport activity was correlated positively with the enrichment factor of the membranes in the apical marker enzyme alkaline phosphatase (r = 0.875, p < 0.01) and negatively correlated with the enrichment factor in basolateral Na+/K+-ATPase (r = -0.665, p < 0.05). Moreover, a functional interaction occurred with Na+/H+ exchange (NHE) consistent with colocation of K+/H+ antiport and apical NHE-3, not basolateral NHE-1. K+/H+ antiport was shown by intracellular pH measurements to be inhibited by arginine vasopressin and 8-bromo-cAMP through cAMP-dependent protein kinase (protein kinase A) activation. These results demonstrate the presence of a K+/H+ antiport mechanism, which is inhibited by arginine vasopressin via protein kinase A, in the apical membrane of the MTAL.
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PMID:Apical location and inhibition by arginine vasopressin of K+/H+ antiport of the medullary thick ascending limb of rat kidney. 932 90

Distribution of the NHE1 and the NHE3 isoforms of Na+/H+ exchanger in the plasma membranes of bovine kidney cortex was analyzed. Fractionation of the plasma membranes by centrifugation on a Percoll density gradient resulted in clear separation of the basolateral membranes (BLM) from the brush-border membranes (BBM), with Na+,K+-ATPase and aminopeptidase M as their respective marker enzymes. Under these conditions, a 110 kDa protein cross-reactive with an anti-NHE1 antibody was detected exclusively in the BLM fractions, while a 90 kDa protein cross-reactive with an anti-NHE3 antibody was detected in the BBM fractions. A conventional Mg2+-precipitation method for obtaining the BBM, which is adequate with rabbit kidney as a starting material, turned out to be inadequate with bovine kidney cortex, since a considerable amount of the 110-kDa NHE1 protein was detected in the bovine kidney BBM fraction prepared by this procedure, together with the 90-kDa NHE3 protein. Percoll density gradient centrifugation is thus strongly recommended for the fractionation of BBM and BLM of bovine kidney cortex. The bovine NHE1 isoform was shown to be unique in that it is far less sensitive to the inhibition by ethylisopropylamiloride than that of other species.
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PMID:Analysis of the distribution of Na+/H+ exchanger isoforms among the plasma membrane subfractions of bovine kidney cortex: reevaluation of methods for fractionating the brush-border and the basolateral membranes. 934 96

The response of the intracellular pH (pHi, measured with BCECF) of the caecal and distal colonic epithelium of guinea pig and of monolayers of HT29 clone 19a cells on the addition of short-chain fatty acids (SCFA) was assessed. Addition of SCFA to the luminal side of these cells had no major effect on pHi, independent of whether the apical Na+/H+ exchange or the apical K+/H+ ATPase was inhibited or not. Addition of SCFA to the serosal side, on the other hand, caused a marked decrease of pHi, followed by an effective regulation back to basal values, and after removal of the acid, the cells became alkalinized. Intracellular pH is mainly regulated by mechanisms in the basolateral membrane. The basolateral Na+/H+ exchanger and the Cl-/HCO3- exchanger were mainly responsible for pHi regulation. Inhibition studies are consistent with a NHE-1 type Na+/H+ exchanger in the basolateral membranes. The apical Na+/H+ exchanger of caecal enterocytes and in HT29 cells, and the apical K+/H+ ATPase in the apical membrane of the distal colon have no or little influence on pHi regulation. The comparison shows that the HT29-19a cell line is an adequate model for studying pHi phenomena of hind gut epithelial cells.
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PMID:Effect of SCFA on intracellular pH and intracellular pH regulation of guinea-pig caecal and colonic enterocytes and of HT29-19a monolayers. 936 78

Vacuolar-type (V) ATPases are thought to be the main determinant of phagosomal acidification. In phagosomes containing mycobacteria, which ostensibly impair the delivery of V-ATPases to the phagosomal membrane, the pH would be expected to be near neutral. This prediction was tested by microfluorescence ratio imaging using macrophages from mice susceptible to mycobacterial infection. Although less acidic than their counterparts containing dead bacteria, phagosomes containing live Mycobacteria bovis were nearly 1 pH unit more acidic than the cytosol, suggesting the existence of alternate H+ transport mechanisms. We therefore investigated whether Na+/H+ exchange (NHE) contributes to phagosomal acidification. Immunoblotting, reverse transcriptase-polymerase chain reaction, and pharmacological studies indicated that NHE1 is the predominant isoform of the exchanger in macrophages. Fractionation revealed that NHE1 is incorporated into the phagosomal membrane, and measurements of pH indicated that it is functional in this location. Nevertheless, acidification of the lumen of phagosomes containing either latex beads or live M. bovis was insensitive to (3-methylsulfonyl-4-piperidinobenzoyl)-guanidine methanesulfonate, a potent inhibitor of NHE1. This may have been due to the absence of an appropriate lumen to cytosol Na+ gradient, because the phagosomal membrane was found to be devoid of Na+/K+ pumps. Unexpectedly, the acidification of M. bovis phagosomes was fully reversed by specific inhibitors of the vacuolar H+-ATPase, suggesting that ATPases are present only transiently or in reduced quantities in the phagosomal membrane. Alternatively, acid equivalents accumulated in endosomes by V-ATPases may be delivered to the mycobacterial phagosome by carrier vesicles devoid of ATPases.
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PMID:Regulation of phagosomal acidification. Differential targeting of Na+/H+ exchangers, Na+/K+-ATPases, and vacuolar-type H+-atpases. 936 53

The kidney plays a major role in the regulation of acid-base balance. This process is mainly dependent on H+ secretion in the tubular lumen. Two acid extruder proteins are involved: the Na+/H+ exchanger and H(+)-ATPase. Studies using in vivo and in vitro microperfusion and isolated membrane vesicles have clearly demonstrated that the Na+/H+ exchanger is the main mechanism regulating H+ secretion/HCO3- reabsorption along the proximal nephron. Moreover, several reports indicate that this protein is involved in intracellular pH (pHi) regulation. Newer studies using molecular biology techniques have identified at least five isoforms of the Na+/H+ exchanger: NHE-1 is the housekeeping isoform, while NHE-3 seems to be implicated in transepithelial acid-base transport, although other isoforms could be involved too. H(+)-ATPase is the major acid extruder protein along the distal nephron, but it is also expressed along the proximal tubule, where a Na(+)-independent bicarbonate reabsorption has been described. There are a few studies indicating that the proton pump participates in pHi regulation, particularly in the presence of a large acid load. Its absence along the distal nephron may be one of the causes of distal tubular acidosis.
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PMID:Update on renal acidification: a physiological view. 938 26

This report presents a study of the effects of the membrane fluidizer, benzyl alcohol, on NHE isoforms 1 and 3. Using transfectants of an NHE-deficient fibroblast, we analyzed each isoform separately. An increase in membrane fluidity resulted in a decrease of approximately 50% in the specific activities of both NHE1 and NHE3. Only Vmax was affected; KNa was unchanged. This effect was specific, as Na+, K+, ATPase activity was slightly stimulated. Inhibition of NHE1 and NHE3 was reversible and de novo protein synthesis was not required to restore NHE activity after washout of fluidizer. Inhibition kinetics of NHE1 by amiloride, 5-(N,N-dimethyl)amiloride (DMA), 5-(N-hexamethyl)amiloride (HMA) and 5-(N-ethyl-N-isopropyl)amiloride (EIPA) were largely unchanged. Half-maximal inhibition of NHE3 was also reached at approximately the same concentrations of amiloride and analogues in control and benzyl alcohol treated, suggesting that the amiloride binding site was unaffected. Inhibition of vesicular transport by incubation at 4 degrees C augmented the benzyl alcohol inhibition of NHE activity, suggesting that the fluidizer effect does not solely involve vesicle trafficking. In summary, our data demonstrate that the physical state of membrane lipids (fluidity) influences Na+/H+ exchange and may represent a physiological regulatory mechanism of NHE1 and NHE3 activity.
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PMID:Inverse relationship between membrane lipid fluidity and activity of Na+/H+ exchangers, NHE1 and NHE3, in transfected fibroblasts. 942 2


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