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)

P-glycoprotein (P-gp), a plasma membrane glycoprotein associated with the multidrug resistance phenotype, is responsible for the ATP-dependent efflux of various amphiphilic drugs. Using membrane vesicles prepared from the multidrug resistant cell line DC-3F/ADX, we studied the perturbation of the basal (i.e. in the absence of drug) and verapamil-dependent P-gp ATPase activities induced by various detergents, at non-solubilizing, as well as at solubilizing, concentrations. The progressive membrane solubilization with increasing detergent concentration was monitored by light scattering and centrifugation experiments. For non-solubilizing detergent concentrations, all tested detergents except DOC induced a partial inhibition of P-gp ATPase activity, which was not correlated with the amount of the various tested detergents incorporated in the membranes. Analysis of the verapamil-induced P-gp activation reveals that P-gp ATPase activity is differently modulated by the various detergents at non-solubilizing concentrations. Thus, specific interactions between P-gp and detergents are more likely to occur rather than a global membrane perturbation. After solubilization by the various tested detergents, the basal P-gp ATPase activity was virtually completely inhibited, except in the presence of CHAPS which was able to preserve this activity at a level comparable to that measured in native membranes. However, the verapamil-induced P-gp ATPase activation was lost during P-gp solubilization by CHAPS, but recovered after dilution of CHAPS below its critical micellar concentration. These observations indicate specific interactions between P-gp and CHAPS molecules within the mixed micelles. On the whole, our data evidencing specific interactions P-gp/detergents are consistent with the location of the drug transport sites on P-gp transmembrane domains.
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PMID:Effects of detergents on P-glycoprotein atpase activity: differences in perturbations of basal and verapamil-dependent activities. 992 70

Human kidney proximal tubule epithelia express the ATP-dependent export pump for anionic conjugates encoded by the MRP2 (cMRP/cMOAT) gene (symbol ABCC2). MRP2, the apical isoform of the multidrug resistance protein, is an integral membrane glycoprotein with a molecular mass of approximately 190 kD that was originally cloned from liver and localized to the canalicular (apical) membrane domain of hepatocytes. In this study, MRP2 was detected in human kidney cortex by reverse transcription-PCR followed by sequencing of a 826-bp cDNA fragment and by immunoblotting using two different antibodies. Human MRP2 was localized to the apical brush-border membrane domain of proximal tubules by double and triple immunofluorescence microscopy including laser scanning microscopy. The expression of MRP2 in renal cell carcinoma was studied by reverse transcription-PCR and immunoblotting in samples from patients undergoing tumor-nephrectomy without prior chemotherapy. Clear-cell carcinomas, originating from the proximal tubule epithelium, expressed MRP2 in 95% (18 of 19) of cases. Immunofluorescence microscopy of MRP2 in clear-cell carcinoma showed a lack of a distinct apical-to-basolateral tumor cell polarity and an additional localization of MRP2 on intracellular membranes. MRP2, the first cloned ATP-dependent export pump for anionic conjugates detected in human kidney, may be involved in renal excretion of various anionic endogenous substances, xenobiotics, and cytotoxic drugs. This conjugate-transporting ATPase encoded by the MRP2 gene has a similar substrate specificity as the multidrug resistance protein MRP1, and may contribute to the multidrug resistance of renal clear-cell carcinomas.
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PMID:Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma. 1036 53

During development, tissue repair, and tumor metastasis, both cell-cell dissociation and cell migration occur and appear to be intimately linked, such as during epithelial "scattering." Here we show that cell-cell dissociation during scattering induced by hepatocyte growth factor (HGF) or activation of the temperature-sensitive v-Src tyrosine kinase in MDCK cells can be blocked by inhibiting the proteasome with lactacystin and MG132. Although both proteins of the tight junction and the adherens junction redistributed during cell scattering, proteasome inhibitors largely prevented this process, resulting in the stabilization of Triton X-100-insoluble tight junction proteins as well as adherens junction proteins at sites of cell-cell contact. Proteasome inhibition also led to a decrease of E-cadherin turnover in (35)S-labeled cells. In addition, proteasome inhibition partly preserved cell polarity, as determined by the subcellular distribution of Na(+),K(+)-ATPase (basolateral marker) and gp135 (apical marker), and the structure of the subcortical actin ring, both of which are normally disrupted during scattering. However, cells were able to establish focal contacts, and single cell migration toward HGF was unaffected by proteasome inhibition in quantitative assays, indicating that cell-cell dissociation during scattering occurs independently of anchorage-dependent cell migration. Thus, a proteasome-dependent step during scattering induced by HGF and pp60(v-Src) appears to be essential for cell-cell dissociation, disassembly of junctional components, and (at least indirectly) it also plays a role in the loss of protein polarity.
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PMID:Cell-cell dissociation upon epithelial cell scattering requires a step mediated by the proteasome. 1045 22

The distribution of K+-pNPPase (Na+,K+-ATPase) activity in the compartments of the Golgi apparatus in neurons of the cerebral cortex of young and adult Wistar rats was studied by ultrastructural cytochemistry. In adult rats, mainly the cis-most cisterna was associated with reaction deposits. In 10- and especially in 15-day-old rats, not only the cis-cisternae, but the cis- and trans-Golgi, as well as components of the Golgi stack, also revealed K+-pNPPase activity. The dynamic changes of K+ -pNPPase localization in the compartments of the neuronal Golgi complexes were discussed with respect to the biochemical evidence concerning the building, assembly and processing of Na+,K+-ATPase as plasma membrane glycoprotein. It was suggested that the high activity in the Golgi complexes seen in 15-day-old rats has to be associated with the advancing myelinization in this period and the necessity of Na+,K+-ATPase equipment of nodes of Ranvier.
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PMID:Subcellular distribution of K+-pNPPase (Na+,K+-ATPase) in the Golgi apparatus of developing rat cortical neurons. 1096 34

The major ectonucleoside triphosphate phosphohydrolase in the chicken gizzard smooth muscle membranes is an ecto-ATPase, an integral membrane glycoprotein belonging to the E-ATPase (or E-NTPDase) family. The gizzard ecto-ATPase is distinguished by its unusual kinetic properties, temperature dependence, and response to a variety of modulators. Compounds that promote oligomerization of the enzyme protein, i.e., concanavalin A, chemical cross-linking agent, and eosin iodoacetamide, increase its activity. Compounds that inhibit some ion-motive ATPases, e.g., sulfhydryl reagents, xanthene derivatives, NBD-halides, and suramin, also inhibit the gizzard ecto-ATPase, but not another E-ATPase, the chicken liver ecto-ATP-diphosphohydrolase, which contains the same conserved regions as the ecto-ATPase. Furthermore, inhibition of the gizzard ecto-ATPase by these compounds as well as detergents is not prevented by preincubation of the membranes with the substrate, ATP, indicating that their interaction with the enzyme occurs at a locus other than the catalytic site. On the other hand, the inhibitory effect of these compounds, except suramin, is abolished or reduced if the membranes are preincubated with concanavalin A. It is concluded that these structurally unrelated modulators exert their effect by interfering with the oligomerization of the ecto-ATPase protein. Our findings suggest that, under physiological conditions, the gizzard smooth muscle ecto-ATPase may exhibit a range of activities determined by membrane events that affect the status of oligomerization of the enzyme.
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PMID:Regulation of chicken gizzard ecto-ATPase activity by modulators that affect its oligomerization status. 1136 71

Pretreatment with the nucleoside antibiotic tunicamycin was found to protect cultured renal epithelial cells in the face of ATP-depletion, in large part by preserving junctional and cellular architecture. Tunicamycin pretreatment of Madin-Darby canine kidney cells not only preserved E-cadherin staining at the plasma membrane, but also inhibited ATP-depletion-mediated E-cadherin degradation. Electron microscopic analysis, together with the preservation of the staining patterns of the tight junction marker ZO-1, the apical/microvillar marker gp135, and basolateral marker Na/K-ATPase suggested that tunicamycin preserved the junctional complex and the polarized epithelial cell phenotype. Tunicamycin pretreatment also prevented reductions in the filamentous actin content of the cells, as well as preserving Golgi architecture. Moreover, a quantitative measure of cell adhesion demonstrated that tunicamycin pretreatment resulted in a fivefold increase in attachment of cells to the substratum (77% versus 16%). Thus, pretreatment with tunicamycin protects polarized epithelial cells from ischemic injury through the preservation of epithelial cell architecture, intercellular junctions, and cell-substratum interactions in the setting of intracellular ATP-depletion.
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PMID:Tunicamycin preserves intercellular junctions, cytoarchitecture, and cell-substratum interactions in ATP-depleted epithelial cells. 1531 95

Rotaviruses constitute a major cause of diarrhea in young mammals. Rotaviruses utilize different integrins as cell receptors, therefore upon their arrival to the intestinal lumen their integrin receptors will be hidden below the tight junction (TJ), on the basolateral membrane. Here we have studied whether the rotavirus outer capsid proteins are capable of opening the paracellular space sealed by the TJ. From the outermost layer of proteins of the rotavirus, 60 spikes formed of protein VP4 are projected. VP4 is essential for virus-cell interactions and is cleaved by trypsin into peptides VP5 and VP8. Here we found that when these peptides are added to confluent epithelial monolayers (Madin-Darby canine kidney cells), VP8 is capable of diminishing in a dose dependent and reversible manner the transepithelial electrical resistance. VP5 exerted no effect. VP8 can also inhibit the development of newly formed TJs in a Ca-switch assay. Treatment with VP8 augments the paracellular passage of non-ionic tracers, allows the diffusion of a fluorescent lipid probe and the apical surface protein GP135, from the luminal to the lateral membrane, and triggers the movement of the basolateral proteins Na+-K+-ATPase, alphanubeta3 integrin and beta1 integrin subunit, to the apical surface. VP8 generates a freeze-fracture pattern of TJs characterized by the appearance of loose end filaments, that correlates with an altered distribution of several TJ proteins. VP8 given orally to diabetic rats allows the enteral administration of insulin, thus indicating that it can be employed to modulate epithelial permeability.
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PMID:The rotavirus surface protein VP8 modulates the gate and fence function of tight junctions in epithelial cells. 1549 77

This study explores the molecular composition of the tight junction (TJ) in human term placenta from normal women and from patients with preeclampsia, a hypertensive disorder of pregnancy. Maternal endothelial dysfunction is a critical characteristic of preeclampsia; hence, we have analyzed its impact on placental vessels. The study concentrates on the TJ because this structure regulates the sealing of the paracellular route. We have found that, in placental endothelial vessels, TJ components include the peripheral protein ZO-1 and the integral proteins occludin and claudins 1, 3, and 5. During preeclampsia, the amounts of occludin and ZO-1 exhibit no significant variation, whereas those of claudins 1, 3, and 5 diminish, suggesting the presence of leakier TJs in the endothelia of the preeclamptic placenta, possibly in response to the decreased perfusion of this organ during preeclampsia. We have unexpectedly found that, in normal placentae, the multinucleated syncytiotrophoblast layer displays claudin 4 at the basal surface of the plasma membrane, and claudin 16 along the apical and basolateral surfaces. The presence of membrane-lined channels that cross the syncytiotrophoblast constituting a paracellular pathway has been determined by transmission electron microscopy and by the co-immunolocalization of claudin 16 with the plasma membrane proteins Na+K+-ATPase and GP135. Since claudin 16 functions as a paracellular channel for Mg2+, its diffuse pattern in preeclamptic placentae suggests the altered paracellular transport of Mg2+ between the maternal blood and the placental tissue.
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PMID:Endothelia of term human placentae display diminished expression of tight junction proteins during preeclampsia. 1650 90

Human NTPDase 2 is a cell surface integral membrane glycoprotein that is anchored to the membranes by two transmembrane domains while the bulk of the protein containing the active site faces the extracellular milieu. It contains 10 conserved cysteine residues in the extracellular domain that are involved in disulfide bond formation and one free cysteine residue, C26, which is located in the N-terminal transmembrane domain. The human NTPDase 2 activity is inactivated by membrane perturbation that disrupts interaction of the transmembrane domains and is inhibited by p-chloromercuriphenylsulfonate (pCMPS), a sulfhydryl reagent. In this report, we show that C26 is the target of pCMPS modification, since a mutant in which C26 was replaced with a serine was no longer inhibited by pCMPS. Mutants in which cysteine residues are placed in the C-terminal transmembrane domain near the extracellular surface were still modified by pCMPS, but the degree of inhibition of their ATPase activity was lower than that of the wild-type enzyme. Thus, loss of the ATPase activity of human NTPDase 2 in the presence of pCMPS probably results from the disturbance of both transmembrane domain interaction and its active site. Inhibition of human NTPDase 2 activity by pCMPS and membrane perturbation is attenuated when the enzyme is cross-linked by glutaraldehyde. On the other hand, NTPDase 2 dimers formed from oxidative cross-linking of the wild-type enzyme and mutants containing a single cysteine residue in the C-terminal transmembrane domain displayed reduced ATPase activity. A similar reduction in activity was also obtained upon intramolecular disulfide formation in mutants that contain a cysteine residue in each of the two transmembrane domains. These results indicate that the mobility of the transmembrane helices is necessary for maximal catalysis.
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PMID:Inhibition of human NTPDase 2 by modification of an intramembrane cysteine by p-chloromercuriphenylsulfonate and oxidative cross-linking of the transmembrane domains. 1865 57

The yeast Saccharomyces cerevisiae vacuolar ATPase (V-ATPase) is a multisubunit complex divided into two sectors: the V(1) sector catalyzes ATP hydrolysis and the V(0) sector translocates protons, resulting in acidification of its resident organelle. Four protein factors participate in V(0) assembly. We have discovered a fifth V(0) assembly factor, Voa1p (YGR106C); an endoplasmic reticulum (ER)-localized integral membrane glycoprotein. The role of Voa1p in V(0) assembly was revealed in cells expressing an ER retrieval-deficient form of the V-ATPase assembly factor Vma21p (Vma21pQQ). Loss of Voa1p in vma21QQ yeast cells resulted in loss of V-ATPase function; cells were unable to acidify their vacuoles and exhibited growth defects typical of cells lacking V-ATPase. V(0) assembly was severely compromised in voa1 vma21QQ double mutants. Isolation of V(0)-Vma21p complexes indicated that Voa1p associates most strongly with Vma21p and the core proteolipid ring of V(0) subunits c, c', and c''. On assembly of the remaining three V(0) subunits (a, d, and e) into the V(0) complex, Voa1p dissociates from the now fully assembled V(0)-Vma21p complex. Our results suggest Voa1p functions with Vma21p early in V(0) assembly in the ER, but then it dissociates before exit of the V(0)-Vma21p complex from the ER for transport to the Golgi compartment.
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PMID:Voa1p functions in V-ATPase assembly in the yeast endoplasmic reticulum. 1879 13


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