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 activity of gastric parietal cells in terms of hydrochloric acid (HCl) secretion is regulated by the interaction of stimulatory substances (e.g. gastrin) and inhibitors (e.g. somatostatin) acting in an endocrine and paracrine mode, as well as luminal factors. In the present study the following parameters were measured: the synthesis (mRNA), storage (tissue peptide concentration) and secretion (plasma peptide concentration) of somatostatin and gastrin following short-term treatment of rats with pentagastrin (acid stimulant), secretin, omeprazole (reduces gastric acidity by inactivating gastric H/K ATPase) and the somatostatin analogue octreotide (reduces gastric acidity by inhibiting both the parietal cell and gastrin). The mRNA coding for H/K ATPase and carbonic anhydrase II (CA II), the two enzymes responsible for the generation of hydrogen ions from the parietal cell, were also quantitated. In response to octreotide, somatostatin peptide and mRNA levels in the fundus rose to 180 +/- 16% (P < 0.001) and 1073 +/- 356% (P < 0.05) of control, respectively. In contrast, octreotide caused a decrease in antral somatostatin peptide and its mRNA did not change significantly. No significant changes in synthesis, secretion or storage of gastrin were observed except for omeprazole induced hypergastrinaemia (580 +/- 76%, P < 0.001). H/K ATPase and CA II mRNA were largely unaffected except for an increase in CA II mRNA following octreotide and a decrease in H/K ATPase mRNA after pentagastrin. These data support the concept of the differential control of antral and fundic somatostatin synthesis and provide evidence for a regulatory loop by which somatostatin can influence its own synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Secretory and biosynthetic responses of gastrin and somatostatin to acute changes in gastric acidity. 852 6

This study demonstrates a pH-dependent inhibition of Mg(2+)- and Ca(2+)-ATPase activities of Nostoc linckia and Chlorella vulgaris exposed to AlCl3, AlF3, NaF and AlCl3+NaF together. AlF3 and the combination of AlCl3+NaF were more inhibitory to both the enzymes as compared with AlCl3 and NaF. Toxicity of the test compounds increased with increasing acidity. Interaction of AlCl3+NaF was additive on N. linckia and C. vulgaris, respectively, at pH 7.5 and 6.8, and synergistic at pH 6.0 and 4.5. In the presence of 60 and 100 microM PO4(3-) an increased NaF concentration (in the AlCl3+NaF combination) was required to produce the same degree of inhibition in ATP synthesis and ATPase activity. Toxicity of fluoroaluminate was reduced in the presence of EDTA and citrate. Except for beryllium to some extent, combinations of cadmium, cobalt, iron, manganese, tin and zinc with fluoride were not as effective as aluminium in inhibiting the ATPase activity. The presence of a 100 kDa protein band in SDS-PAGE of both control as well as AlCl3+NaF-treated samples suggested that AlF4- inhibits the ATPase activity by acting as a functional barrier without affecting the structure of the enzyme.
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PMID:Impact of aluminium, fluoride and fluoroaluminate complex on ATPase activity of Nostoc linckia and Chlorella vulgaris. 869 79

The presence of vacuolar H(+)-ATPase (V-ATPase) on exocytotic granules in eosinophils and the role of this enzyme in exocytosis were explored in this study. Antibody against 116-kd subunit of V-ATPase positively stained eosinophil granules in immunofluorescence analysis. When eosinophil lysate was extracted immunomagnetically with the same antibody, the extracted fraction contained a considerable amount of eosinophil peroxidase, a marker of eosinophil-specific granules, which indicates that V-ATPase was present on the membranes of eosinophil exsosomal granules. The pH of the eosinophil granules, measured fluorometrically with acridine orange as a delta pH-sensitive dye, was estimated to be 5.1. The acidity of the eosinophil granules was perturbed by bafilomycin A1, a potent selective inhibitor of V-ATPase, which indicates that the low pH of these granules is maintained by V-ATPase activity. BafilomycinA1 and NH4Cl, both of which raise the intragranular pH to neutral, inhibited the eosinophil peroxidase exocytosis induced by platelet-activating factor. These agents did not, however, affect the changes in cytosolic free calcium concentration [Ca2+]i induced by platelet-activating factor. These observations suggest that bafilomycin A1 inhibited a delta pH-requiring step in eosinophil exocytosis that was preceded by the [Ca2+]i transient in the signal transduction pathway, and, hence, the findings suggest the pivotal role of V-ATPase in maintaining intragranular pH and its function of eosinophil exosomal granules.
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PMID:The role of vacuolar H(+)-ATPase in the control of intragranular pH and exocytosis in eosinophils. 894 Dec 14

Gastro-oesophageal reflux disease (GORD) is a very common disorder of upper gastro-intestinal motility, differing widely in severity and prognosis. Medical therapy of GORD has involved antacids, alginates, prokinetic agents and antisecretory compounds, primarily H2 receptor antagonists and proton pump inhibitors. Knowledge of the pharmacokinetics of these compounds is important, to optimise the therapeutic benefit in each patient. GORD patients are often elderly and pharmacokinetics are move variable in this group. Furthermore, they often suffer from other diseases needing medical therapy and may need a combination of drugs to heal reflux oesophagitis and relieve reflux symptoms. The ideal therapy for GORD will have linear pharmacokinetics, a relatively long plasma half-life (t1/2), a duration of action allowing once daily administration, and a stable effect independent of interactions with food, antacids and other drugs. Over-the-counter antacids and alginates are widely used, buy may affect absorption of H2 receptor antagonists like cimetidine and ranitidine. Aluminium-containing antacids may, over time, cause toxicity in patients with renal insufficiency. In the treatment of GORD, cisapride presents important advantages over earlier prokinetic compounds, with a longer plasma t1/2, low penetration of the blood-brain barrier and fewer adverse effects. The group of H2 receptor antagonists is still the most frequently use therapy for GORD. Linear pharmacokinetics make dose adjustments easy and safe. In individual patients, suppression of gastric secretion is related to the area under the plasma concentration-time curve (AUC), but there is wide interindividual variation in the effect of the same oral dose. Only with frequent administration and high doses will acid suppression approximate that of proton pump inhibitors. Tolerance, with loss of effect over time, however, is most pronounced in this situation. H2 receptor antagonists seem well suited for on-demand treatment of reflux symptoms, due to the rapid onset of effect and a decrease likelihood of the development of tolerance. Effervescent formulations provide more rapid absorption and almost immediate clinical effect. Cimetidine, however, causes interference with the metabolism of several other drugs in common use. In elderly patients elimination is delayed and in patients with renal insufficiency, dose reductions of all H2 receptor antagonists are recommended. The most effective medical therapy for any severity of GORD, particularly in severe oesophagitis, are the proton pump inhibitors. The substituted benzimidazoles (omeprazole, lansoprazole and pantoprazole), are prodrugs which once trapped and activated in the acid milieu of the gastric glands potently suppress gastric secretion of acid and pepsin. Their long duration of action, more related to the slow turnover of parietal cell H(+)-K+ ATPase molecules, allows once daily administration in most patients. Interindividual variation in bioavailability sometimes calls for higher doses or twice daily administration. Acid suppression is closely related to the AUC. Omeprazole is prone to interaction with the metabolism of other drugs, some of which may e be clinically important. Lansoprazole seems to have an earlier onset of action than omeprazole, ascribed to higher bioavailability during the first days of treatment. Proton pump inhibitors have a slow onset of action, which makes them unsuited for on-demand therapy. Clinical practice in GORD calls for the use of not one but several substances, according to the severity and symptom pattern of the patient. Pharmacokinetic optimisation in the treatment of GORD is a question of selecting the most suitable substances and administration schemes within each group. Cisapride is superior to other prokinetics in terms of longer plasma t1/2 and less toxicity. Amongst H2 receptor antagonists, the more long-acting compounds, ranitidine and famotidine, will improve acidity control througho
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PMID:Pharmacokinetic optimisation in the treatment of gastro-oesophageal reflux disease. 911 86

ATP-driven acidification of internal compartments of Trypanosoma cruzi epimastigotes was assayed spectrophotometrically with Acridine Orange and cells permeabilized with filipin. H+-ATPase activity was not inhibited fully by either 500 nM concanamycin A or 500 microM orthovanadate, but a combination of 5 nM concanamycin A and 25 microM vanadate completely inhibited activity, suggesting the operation of separate V-type (concanamycin-sensitive) and P-type (vanadate-sensitive) H+-ATPase activities in the permeabilized cells. This was supported by different kinetics of Acridine Orange uptake seen in the presence of the different inhibitors, and by different optimal protein (cell) concentrations for the two apparent activities. The use of different buffers further distinguished the ATPases. The V-H+-ATPase activity was stimulated by K+ and inhibited by a lack of anions or the replacement of Cl- with gluconate. The P-type H+-ATPase activity was not affected by a lack of Cl- or K+ but was substantially inhibited in a largely anion-free buffer. This inhibition could be annulled by the addition of the K+ ionophore valinomycin, which probably acted via the establishment of a countercurrent efflux of K+ from the compartment containing the P-type H+-ATPase and the relief of the potential difference generated by the electrogenic proton pump. Valinomycin showed some stimulation of P-type activity in all buffers tested, but its effects on V-H+-ATPase activity were at best transient except in a K+-free buffer, which suggested that the V-H+-ATPase was located in an organelle with relatively low [K+] that was different from that which accommodated the P-type activity. On the basis of acidity and K+ content, these organelles might correspond, in part at least, to the acidocalcisomes (V-H+-ATPase activity) and the reservosomes (P-type activity) previously identified in these cells. Both activities could also be found in the human-infective forms of the parasite, amastigotes and trypomastigotes, but the P-type activity was relatively weak in these cells types, which is correlated with a lack of reservosomes in these forms.
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PMID:Two types of H+-ATPase are involved in the acidification of internal compartments in Trypanosoma cruzi. 953 1

Eukaryotic cells have developed an array of endomembrane systems that have differentiated to carry out various functions. They are involved in the pathways of endocytosis and exocytosis, and have an acidic lumenal pH ranging from 4.5 to 6.5. This review describes recent studies on the animal cell organelles and how they relate to the well studied systems of yeast. We focus mainly on (i) the primary proton pump (vacuolar type H+-ATPase) and other factors that establish acidic pH, and (ii) functions of the organelles as related to lumenal acidity.
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PMID:Diverse roles of single membrane organelles: factors establishing the acid lumenal pH. 968 12

Three wild-type strains of Saccharomyces cerevisiae, viz. K, Y55 and sigma 1278b, two mutants lacking one or both of the putative K+ transporters, trk1 delta and trk1 delta trk2 delta, and a mutant in the plasma membrane H(+)-ATPase, viz. pma1-105, were compared in their extracellular acidification following addition of glucose and subsequent addition of KCl; in ATPase activity in purified plasma membranes; and in respiration on glucose. The glucose-induced acidification was the greater the higher the respiratory quotient, i.e. the higher the anaerobic metabolism. A markedly lower acidification was found in the ATPase-deficient pma1-105 strain but also in the TRK-deficient double mutant. The acidification pattern after addition of KCl corresponds to expectations in the TRK mutants; however, a similarly decreased acid production was found in the ATPase-deficient mutant pma1-105. The highest rate of ATP hydrolysis in vitro was found with the trk1 delta trk2 delta mutant where glucose-, as well as KCl-induced acidification were lowest. Likewise, the pma1-105 mutant with extremely low acidification showed only a minutely lower ATP hydrolysis than did its parent Y55 strain. Apparently, several different sources of acidity are involved in the glucose-induced acidification (including extrusion of organic acids); in fact, contrary to the general belief, the H(+)-ATPase may play a minor role in this process in some strains.
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PMID:Different sources of acidity in glucose-elicited extracellular acidification in the yeast Saccharomyces cerevisiae. 986 51

Gastric somatostatin (SRIF) regulates gastric acidity by inhibiting gastric acid and gastrin secretion. SRIF secretion is increased by gastric acidity and also directly by regulators of gastric acid secretion such as gastrin. This direct effect has not been described in the developing animal, nor have the roles of intermediaries such as histamine and gastric acidity been defined. The present study aimed to establish the regulatory role of gastrin and histamine during development on SRIF secretion and also to determine whether the effects of gastrin and histamine are independent of gastric pH. Pentagastrin and histamine were infused on separate occasions into fetal sheep, newborn lambs, and 28-day-old lambs. To determine the roles of endogenous histamine and gastric pH, ranitidine (a histamine-2 receptor antagonist) and omeprazole (a H+/K+ ATPase inhibitor) were coinfused with the agonists. Plasma SRIF and gastrin concentrations were measured by RIA. Pentagastrin stimulated SRIF secretion in the fetus after 131 days of gestation (term is 147 days), whereas stimulation by histamine was effective only after birth. The SRIF stimulatory effect of pentagastrin in 28-day-old lambs was abolished by ranitidine, which also reduced this effect in the adult sheep. This inhibitory effect of ranitidine was shown to be a result of blockade of stimulatory H2 receptors, because in the adult blockade of acid secretion with omeprazole failed to attenuate the response of histamine. These results indicate that in the fetus, gastrin receptors, but not histamine receptors, are functionally involved in the stimulation of SRIF secretion. After birth, both gastrin and histamine stimulate SRIF, but the effect of gastrin is mediated at least in part by the release of endogenous histamine. These responses occur independently of changes in gastric acidity, supporting the concept of a direct negative feedback between SRIF and gastrin.
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PMID:Developmental regulation of gastric somatostatin secretion in the sheep. 992 83

Distal renal tubular acidosis is a common health problem in northeastern Thailand, with the population background of the low potassium intake, low urine citrate, and decreased red blood cell Na-K adenosine triphosphatase (ATPase) activity and the environment of the high soil vanadium. The disease is usually seen in the people with low socioeconomic status in summer. The patients have decreased gastric acidity and low urine potassium. There are varying degrees of renal function from normal to impairment. Gastric hypoacidity is an important clue. Defects in H-K ATPase and anion exchange (AE2) mechanism are considered. The urine vanadium is higher in the patients than that of normal rural northeastern villagers. Inhibition of H-K ATPase by vanadium seems possible and requires more supporting evidence. AE1 gene mutation is noted in few patients. The cause of dRTA is not apparent. The AE2 gene and H-K ATPase gene remain to be studied. Both environmental and genetic factors could contribute to the pathogenesis of the disease.
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PMID:Environmental distal renal tubular acidosis in Thailand: an enigma. 1035 13

Rabeprazole sodium is a new substituted benzimidazole proton pump inhibitor with several differences compared with existing proton pump inhibitors. In vitro and animal studies have demonstrated that rabeprazole is a more potent inhibitor of H+,K(+)-ATPase and acid secretion than omeprazole, and is a more rapid inhibitor of proton pumps than omeprazole, lansoprazole, or pantoprazole. This probably reflects rabeprazole's faster activation in the parietal cell canaliculus. In human studies, once-daily doses of 5-40 mg of rabeprazole inhibit gastric acid secretion in a dose-dependent fashion. A once-daily dose of 20 mg has consistently achieved profound decreases in 24-h intragastric acidity in single and repeat dosing studies, in healthy volunteers and patients with either peptic ulcer disease or gastro-oesophageal reflux disease. Significantly greater decreases in intragastric acidity are achieved on day 1 of dosing with rabeprazole 20 mg than with omeprazole 20 mg. As with other proton pump inhibitors, rabeprazole has in vitro antibacterial activity against Helicobacter pylori, with greater activity against this organism than either lansoprazole or omeprazole. In addition to inhibiting bacterial urease activity, rabeprazole binds to several molecules on H. pylori. Clinical trials are needed to assess the clinical importance of these findings, as well as to assess whether the potential advantages of rabeprazole result in clinical benefit for patients with acid-related diseases.
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PMID:Review article: the pharmacology of rabeprazole. 1049 23


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