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)

In rabbit alveolar macrophages, recovery of intracellular pH (pHi) from acid loads to pHi values > or = 6.8 at an extracellular pH (pHo) of 7.4 (nominal absence of CO2-HCO3-) is insensitive to amiloride, an inhibitor of Na(+)-H+ exchange, and abolished by bafilomycin A1, an inhibitor of vacuolar-type H(+)-ATPase [A. Bidani, S.E.S. Brown, T.A. Heming, R. Gurich, and T.D. Dubose, Jr. Am. J. Physiol. 257 (Cell Physiol. 26): C65-C76, 1989; A. Bidani and S. E. S. Brown. Am. J. Physiol. 259 (Cell Physiol. 28): C586-C598, 1990]. To further evaluate the roles of Na(+)-H+ exchange and H(+)-ATPase activity in pHi regulation in rabbit alveolar macrophages, we have investigated the effects of amiloride and bafilomycin over a greater range of pHi (6.3-7.0) and pHo (5.0-7.4). The results indicate that rabbit alveolar macrophages possess H(+)-ATPase and a Na(+)-H+ antiporter, both of which are activated by decrements in pHi. However, in all cases, H(+)-ATPase activity exclusively determined basal pHi and was the principal mechanism (> 50%) for pHi recovery from intracellular acid loads. The pHi set point for activation of Na(+)-H+ exchange was approximately 6.8 at pHo of 7.4 and approximately 6.5 at pHo of 6.8. Na(+)-H+ exchange did not contribute significantly to pHi recovery at acid-loaded pHi above these set points. At pHo of 7.4 and pHi > or = 6.8, pHi recovery displayed an activation energy of approximately 11,000 kcal/mol and temperature coefficient of approximately 2.1, which are consistent with an energy-dependent process (i.e., H+ pump).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:pHi regulation in alveolar macrophages: relative roles of Na(+)-H+ antiport and H(+)-ATPase. 802 57

The role of protein kinase C in the regulation of vacuolar-type H(+)-ATPase (V-ATPase) activity was studied in thioglycolate-elicited mouse peritoneal macrophages. Acid-loaded macrophages suspended in a Na(+)- and HCO(3-)-free K(+)-medium containing Zn2+, a H(+)-conductance blocker, exhibited an initial intracellular pH recovery rate of 0.33 +/- 0.04 pH/min (n = 9). Pretreatment with 12-O-tetradecanoyl phorbol 13-acetate (TPA) or mezerein for as little as 3 min induced a marked (82%) increase in the initial pH recovery rate. Stimulation was prevented by the V-ATPase inhibitor, bafilomycin A1 (200 nM) indicating that the effect of the protein kinase C agonist was via augmentation of proton pump activity. The protein kinase C inhibitor, staurosporine (100 nM) completely blocked the stimulatory effects of TPA and mezerein, suggesting involvement of protein kinase C. In keeping with this notion, the inactive analogue of TPA, 4-phorbol didecanoate did not stimulate recovery from an acid load. Extracellular pH determinations revealed that the observed increase in cytosolic pH recovery rate by the protein kinase C agonists was due to increased extrusion of protons from the cells, likely through V-ATPases located in the plasma membrane. Considered together, these data demonstrate regulation of plasmalemmal V-ATPase-mediated proton extrusion by protein kinase C.
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PMID:Protein kinase C activation accelerates proton extrusion by vacuolar-type H(+)-ATPases in murine peritoneal macrophages. 806 29

Omeprazole is an inhibitor of gastric H+,K(+)-ATPase. Although the major proton transport of osteoclast is mediated by a vacuolar-type H(+)-ATPase which is different from the gastric H+,K(+)-ATPase, in vitro studies have demonstrated that omeprazole inhibits bone resorption. In this study, the effect of omeprazole on bone resorption was evaluated in patients who had a history of gastric ulcer and were treated with maintenance doses of H2 blocker without any gastric complaints at the study time. H2-blocker administration was changed to omeprazole treatment in the study group and to no treatment in the control group. Urinary excretion of hydroxyproline and calcium decreased after omeprazole treatment in the study group. Serum intact PTH, alkaline phosphatase, osteocalcin, and tartrate-resistant acid phosphatase (TRAP) increased in this group. In the control group, there were not any changes in these parameters. The discrepancy between serum TRAP and urinary excretion of hydroxyproline and calcium in the study group was thought to be due to the suppression of bone resorption by omeprazole, which probably interfered the acidification at resorption lacunae and resulted in the inactivation of TRAP and other lysosomal enzymes. The results of our study suggest the possibility that the specific inhibitors of the osteoclastic proton pump (such as bafilomycins) will more effectively suppress bone resorption and be useful for the treatment of metabolic bone diseases with increased bone resorption.
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PMID:Effect of omeprazole, an inhibitor of H+,K(+)-ATPase, on bone resorption in humans. 810 18

Intrahepatic bile duct epithelial cells contribute to bile formation by hormone-dependently secreting HCO3- to bile and H+ to periductular fluid. The present study was undertaken to determine whether the secretin-induced H+ secretion is due to activation of a H(+)-ATPase or Na(+)-H+ exchange. H+ secretion was estimated from the rate of intracellular pH (pHi) recovery after acid loading (24 mM NH4Cl) of microdissected bile ductules from pig liver mounted in a flow-through chamber on the stage of a microscope. pHi was measured from an estimated average of 10-15 epithelial cells using the fluorescent pHi indicator 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein and dual-wavelength excitation of fluorescence. The ducts were superfused with HCO3(-)-free N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffers. We found that secretin induced net H+ secretion of 4.53 +/- 0.7 mumol.ml cell volume-1 x min-1. This H+ secretion was blocked by 10(-6) M bafilomycin A1 but was unaffected by Na+ substitution with choline in the superfusion buffer. The experiments also showed that bafilomycin A1 did not block Na(+)-H+ exchange. The secretin-induced H+ secretion is probably caused by a vacuolar-type H(+)-ATPase and may constitute an important element of the cellular mechanisms causing secretin-dependent ductular HCO3- secretion into bile.
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PMID:Secretin causes H+ secretion from intrahepatic bile ductules by vacuolar-type H(+)-ATPase. 823 55

Vacuolar-type H(+)-ATPase from adrenal chromaffin granules was found to be sensitive to omeprazole, a known gastric H+/K(+)-ATPase inhibitor, the concentration required for 50% inhibition being 80 microM freshly-prepared and 12 microM acid-treated reagent. ATP and ADP protected the enzyme from inhibition by omeprazole. The activity of the inhibited enzyme was restored by the addition of reduced glutathione. Omeprazole protected the enzyme from inhibition by N-ethylmaleimide and its binding to the subunit A. As subunit A has a nucleotide binding site(s) and as a cysteine residue is involved in the inhibition by N-ethylmaleimide, these results suggested that the two sulfhydryl reagents bind to the same cysteine residue near the nucleotide binding domain in the subunit A, resulting in inactivation of vacuolar-type H(+)-ATPase.
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PMID:Evidence for a common binding site for omeprazole and N-ethylmaleimide in subunit A of chromaffin granule vacuolar-type H(+)-ATPase. 824 Mar 46

We investigated effects of bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase (V-ATPase), and its analogues on proliferation of various cultured cells. The proliferation of the various cell lines was suppressed by adding bafilomycin A1 to the culture medium. This inhibitory effect appeared at a concentration of nanomolar order and was dose dependent. Although the suppression was reversible, the drug exerted not only suppression of the proliferation but also death to some cell lines. Drug concentration required for 50% inhibition of the cell proliferation during 48 h differed markedly depending on cell species and the sensitivity appears to increase by the transformation of the cells. Two derivatives of concanamycin A, an analogue of bafilomycin A1, also inhibited strongly V-ATPase in vitro and in vivo, and simultaneously cell proliferation. Two concanamycin A derivatives which have lost inhibitory effect on V-ATPase lost inhibitory effect on cell proliferation as well. These results suggest that V-ATPase is involved in the machinery maintaining the cell proliferation.
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PMID:Inhibitors of vacuolar-type H(+)-ATPase suppresses proliferation of cultured cells. 825 55

Energy dependence for uptake of 4-methyphenylpyridinium (MPP+), a neurotoxin causing Parkinsonism-like symptoms, by adrenal chromaffin granule membrane vesicles and brain synaptic vesicles was studied. The compound was actively taken up by the chromaffin vesicles dependent on hydrolysis of ATP with a Km value of 22 microM and maximum velocity of 2.9 nmol/min/mg protein. The uptake was sensitive to reserpine (1 microM) and bafilomycin (50 nM) (inhibitors of the vesicular monoamine transporter and vacuolar-type H(+)-ATPase, respectively) and substrates for monoamine transporters, but insensitive to imipramine (an inhibitor of the monoamine transporter present in the plasma membrane). The uptake was greatly reduced upon dissipation of the proton gradient by ammonium ion or nigericin with KCl, but stimulated 1.6-fold by valinomycin plus K+. Dissipation of the proton gradient also induced rapid efflux of MPP+ from the vesicles. The MPP+ (monoamine) transporter was solubilized from chromaffin vesicles and reconstituted into liposomes with purified bacterial F0F1-ATPase. MPP+ was taken up by the liposomes coupled with ATP hydrolysis by F0F1, and the uptake was sensitive to reserpine, dissipation of the proton gradient, and azide. Brain synaptic vesicles also accumulated MPP+, showing similar kinetics, inhibitor sensitivities, and energy coupling to those of chromaffin vesicles. Furthermore, MPP+ inhibited the uptake of dopamine without affecting the uptake of glutamate or gamma-aminobutyrate. These results indicated that MPP+ was taken up through the reserpine-sensitive monoamine transporter into chromaffin vesicles and synaptic vesicles and that the energy for accumulation of MPP+ was supplied as a proton gradient (acidic inside) established by H(+)-ATPase.
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PMID:Uptake of the neurotoxin, 4-methylphenylpyridinium, into chromaffin granules and synaptic vesicles: a proton gradient drives its uptake through monoamine transporter. 837 64

The effects of neuron blockers on neurotransmitter accumulation in synaptic vesicles were investigated. Upon addition of ATP, brain synaptic vesicles accumulated chlorpromazine, haloperidol, and propranolol against concentration gradients of more than 100-fold. Bioenergetic analysis indicated that the transmembrane pH gradient (delta pH) established by the vacuolar-type H(+)-ATPase is a direct driving force for these uptakes. Essentially the same results were obtained with vesicles from bovine adrenal chromaffin granules and proteoliposomes reconstituted with purified vacuolar H(+)-ATPase, indicating that the energy-dependent accumulation is due to diffusion and does not involve transport carriers specific for the blockers. Incubations of the two organelles with the blockers resulted in dissipation of delta pH and slight increase of membrane potential (delta psi) without affecting ATPase activity. Under the same conditions, uptake of dopamine or gamma-aminobutyrate (delta pH-driven transport) was inhibited by neuron blockers, whereas uptake of glutamate (delta psi-driven transport) was slightly stimulated. Thus, neuron blockers inhibited delta pH-driven uptake of neurotransmitter by dissipating the driving force. These results strongly suggest that synaptic vesicles are one of the target sites of neuron blockers.
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PMID:Energy-dependent accumulation of neuron blockers causes selective inhibition of neurotransmitter uptake by brain synaptic vesicles. 837 65

N-ethylmaleimide-sensitive fusion protein (NSF), a protein necessary for vesicular docking and/or fusion, was detected immunohistochemically in pinealocytes. NSF was distributed similarly to synaptophysin and vacuolar-type H(+)-ATPase (V-ATPase), marker proteins for synaptic-like microvesicles (MVs) abundantly present in pinealocytes. A subcellular fractionation study indicated that .> 95% of NSF was present as a membrane-bound form and that some NSF was associated with MVs. Like neuronal NSF, the protein was not solubilized from membranes with either 2 mM Mg-ATP or 2% sodium carbonate, suggesting that NSF was tightly bound to the membranes. NSF was also detected in purified MVs from bovine posterior pituitaries. Since MVs are the organelles in which transmitters are stored, these results suggest that NSF is involved in the MV-mediated exocytosis of transmitters from endocrine cells.
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PMID:Localization of N-ethylmaleimide-sensitive fusion protein in pinealocytes. 854 75

Maintenance of cytoplasmic pH (pHi) within a narrow physiological range is crucial to normal cellular function. This is of particular relevance to phagocytic cells within the acidic inflammatory microenvironment where the pHi tends to be acid loaded. We have previously reported that a vacuolar-type H(+)-ATPase (V-ATPase) situated in the plasma membrane of macrophages and poised to extrude protons from the cytoplasmic to the extracellular space is an important pHi regulatory mechanism within the inflammatory milieu. Since this microenvironment is frequently characterized by the influx of cells known to release inflammatory cytokines, we performed studies to examine the effect of one such mediator molecule, interleukin-1 (IL-1), on pHi regulation in peritoneal macrophages. IL-1 caused a time- and dose-dependent increase in macrophage pHi recovery from an acute acid load. This effect was specific to IL-1 and was due to enhanced plasmalemmal V-ATPase activity. The increased V-ATPase activity by IL-1 occurred following a lag period of several hours and required de novo protein and mRNA synthesis. However, Northern blot analysis revealed that IL-1 did not exert its effect via alterations in the levels of mRNA transcripts for the A or B subunits of the V-ATPase complex. Finally, stimulation of both cAMP-dependent protein kinase and protein kinase C was required for the stimulatory effect of IL-1 on V-ATPase activity. Thus, cytokines present within the inflammatory milieu are able to modulate pHi regulatory mechanisms. These data may represent a novel mechanism whereby cytokines may improve cellular function at inflammatory sites.
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PMID:Interleukin-1 increases vacuolar-type H+-ATPase activity in murine peritoneal macrophages. 856 51


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