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 efflux of GSH has been shown previously to be a saturable process in both isolated rat hepatocytes and perfused liver, suggesting a carrier-mediated transport mechanism. The possibility in hormonal regulation of this process has been raised by recent reports. Our present work examined the role of hormones known to affect intracellular signal transduction mechanisms on GSH efflux in cultured rat hepatocytes and perfused rat livers. We found that cAMP-dependent factors, such as cholera toxin (CT), dibutyryl cAMP, forskolin, and glucagon all stimulated GSH efflux in cultured rat hepatocytes. The efflux kinetics were compared in cultured cells incubated with or without CT; the stimulation of GSH efflux was related to a near doubling of the Vmax while exhibiting no significant alteration of the Km. The increase in intracellular cAMP level associated with the threshold for this stimulatory effect was 25% above control. The stimulatory effect of CT could not be blocked by cyclohexamide pretreatment or reversed by colchicine treatment. The stimulatory effect of glucagon was abolished in the presence of ouabain but not in the presence of barium. On the other hand, hormones which act through Ca2+ and protein kinase C, such as phenylephrine and vasopressin, had no effect on GSH efflux in the cultured cells. In the perfused liver model, glucagon (10 nM) and dibutyryl cAMP (8 microM) stimulated sinusoidal GSH efflux to 130 and 144% of control values, respectively, and increased bile flow while not affecting biliary GSH efflux. Finally, the physiological significance of glucagon-mediated stimulation of sinusoidal GSH efflux was assessed by both plasma GSH and glucose levels in response to in vivo glucagon infusion. The threshold dose of glucagon for significant increase in plasma GSH (5.21 pmol/min) was lower than for glucose (15.61 pmol/min). At the highest glucagon infusion rate (261 pmol/min), plasma GSH level doubled while glucose level increased 80%. In conclusion, increased cAMP stimulates GSH efflux in cultured rat hepatocytes and perfused livers. The stimulatory effect of cAMP is exerted at the sinusoidal pole and appears to be mediated by hyperpolarization of hepatocytes by stimulation of Na(+)-K(+)-ATPase. In vivo studies confirmed the importance of cAMP-mediated stimulation of sinusoidal GSH efflux as it resulted in significant elevation of the plasma GSH level.
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PMID:Hormonal regulation of glutathione efflux. 216 79

The cellular mechanisms by which nephrotoxic heavy metals injure the proximal tubule are incompletely defined. We used extracellular electrodes to measure the early effects of heavy metals and other sulfhydryl reagents on net K+ and Ca2+ transport and respiration (QO2) of proximal tubule suspensions. Hg2+, Cu2+, and Au3+ (10(-4)M) each caused a rapid net K+ efflux and a delayed inhibition of QO2. The Hg2(+)-induced net K+ release represented passive K+ transport and was not inhibited by barium, tetraethylammonium, or furosemide. Both Hg2+ and Ag+ promoted a net Ca2+ uptake that was nearly coincident with the onset of the net K+ efflux. A delayed inhibition of ouabain-sensitive QO2 and nystatin-stimulated QO2, indicative of Na+, K(+)-ATPase inhibition, was observed after 30 sec of exposure to Hg2+. More prolonged treatment (2 min) of the tubules with Hg2+ resulted in a 40% reduction in the CCCP-uncoupled QO2, indicating delayed injury to the mitochondria. The net K+ efflux was mimicked by the sulfhydryl reagents pCMBS and N-ethylmale-imide (10(-4) M) and prevented by dithiothreitol (DTT) or reduced glutathione (GSH) (10(-4) M). In addition, both DTT and GSH immediately reversed the Ag(+)-induced net Ca2+ uptake. Thus, sulfhydryl-reactive heavy metals cause rapid, dramatic changes in the membrane ionic permeability of the proximal tubule before disrupting Na+, K(+)-ATPase activity or mitochondrial function. These alterations appear to be the result of an interaction of the metal ions with sulfhydryl groups of cell membrane proteins responsible for the modulation of cation permeability.
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PMID:Sulfhydryl-reactive heavy metals increase cell membrane K+ and Ca2+ transport in renal proximal tubule. 230 68

Nitroimidazole compounds are effective radiosensitizers, but neurotoxic side effects prevent their clinical use. Studying the effect of misonidazole, metronidazole and two of its derivatives, 4.5-NO2-METRO and 4-NO2-METRO, on red blood cell, it was recently demonstrated that these compounds inhibit the red cell membrane (Na+-K+) ATPase and decrease the fluidity of the membrane bilayer. In order to extend these observations and to achieve a more complete interpretation, four additional investigations were selected: the (Ca++-Mg++)ATPase activity, the anion channel (band 3 protein) kinetics, the susceptibility of the phospholipids to peroxidation, and their influence on the concentration of reduced glutathione (GSH). The activity of the (Ca++-Mg++)ATPase and its stimulation by calmodulin were decreased by all four drugs, but the anion transport kinetics were unaltered. No lipid peroxidation could be detected, as estimated by the production of malonyldialdehyde. The red cell GSH was depleted by 4.5-NO2-METRO, probably due to the formation of a complex between GSH and the drugs [Varghese 1983]. The mechanism of the inhibition of the ATPases is not yet clearly apparent; it is presently sought in a direct interaction of the drugs with some thiol reactive groups of the ATPases.
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PMID:The influence of nitroheterocyclic radiosensitizers on the membrane of red blood cells. 243 Sep

Pancreatic duct fragments were isolated from rat and hamster pancreas and were cultured in an agarose matrix for up to 8 weeks (rat) or 20 weeks (hamster). The fragments consisted predominantly of duct epithelium, lesser numbers of stromal and atrophied acinar cells, and small numbers of islet cells. Hamster ducts averaged 3 micrograms protein per duct while rat ducts averaged 1 microgram, and the protein:DNA ratio of both types of ducts was less than that of whole pancreas. Estimated average duct yields of 6% (hamster) and 1% (rat) were based on the protein content of the ducts. Duct viability was shown by the incorporation of 3H-thymidine and 3H-leucine into bulk DNA and protein and by autoradiography. gamma-Glutamyl transferase and (Na + K)-ATPase specific activities were slightly elevated while amylase was depressed in the ducts when compared with whole pancreas in both species. gamma-Glutamyl transferase was localized histochemically in both duct epithelium and in surviving acinar tissue, as seen in vivo. Amylase was shown by immunohistochemistry to be present within duct lumina and in atrophied acini and their lumina. Alkaline phosphatase and Mg-ATPase specific activities were elevated in the hamster, but reduced in the rat, when compared with whole pancreas. Hamster alkaline phosphatase and Mg-ATPase were localized by histochemistry to the duct stroma, where these enzymes are not detected in vivo. Carbonic anhydrase was found in the duct epithelium of both species, as in vivo, as well as in the duct stroma, unlike in vivo. Acid glycosaminoglycans, as revealed by alcian blue staining, were found at the apical surfaces and in the lumina of both kinds of ducts. Glutathione-S-transferase and glucose-6-phosphate dehydrogenase were elevated in rat ducts, but not in hamster ducts. The polypeptide compositions of cultured ducts, freshly isolated pancreatic islets, and whole pancreas were compared by one-dimensional sodium dodecyl sulfate polyacrylamide gradient gel electrophoresis. No duct-specific polypeptides were observed; the ducts were characterized mainly by the reduction or absence of polypeptides, including some zymogens, seen in whole pancreas.
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PMID:Biochemical and histochemical characterization of cultured rat and hamster pancreatic ducts. 244 50

The effect of ultraviolet light-B (UVB) irradiation on the activity of prostaglandin (PG) D synthetase was investigated in adult rat skin. Rats were irradiated with 500 mJ/cm2 of UVB, and PGD synthetase activity was determined in 100,000 g supernatant of the homogenate of rat skin in the presence of glutathione (GSH) before and 3, 6, 12, and 24 h after irradiation. The PGD synthetase activity was decreased time dependently, and within 24 h after UVB irradiation it had dropped to 50% of the control level before irradiation. In contrast, the synthesizing activities of PGE2 and PGF2 alpha were unaffected by UVB irradiation. The reduction of PGD synthetase activity after UVB irradiation was much more prominent in the epidermis than in the dermis, which was separated by heat treatment (55 degrees C, 30 sec). Immunohistochemical studies, using anti-(rat spleen PGD synthetase) antibody, revealed that the number of immunopositive cells, which were identified as Langerhans cells, decreased in the basal layer of the epidermis 24 h after UVB irradiation. These results, together with the reduction of ATPase positive cells in the epidermis after UVB irradiation, suggest that the decrease of PGD synthetase activity in rat skin by UVB irradiation is, at least in part, due to the reduced Langerhans cell population in the basal layer of the epidermis.
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PMID:Effect of ultraviolet irradiation on the activity of rat skin prostaglandin D synthetase. 252 10

Reactive disulfide compounds (RDSs) with a pyridyl ring adjacent to the S-S bond such as 2,2'-dithiodipyridine (2,2'-DTDP), 4,4'-dithiodipyridine, and N-succinimidyl 3(2-pyridyldithio)propionate (SPDP) trigger Ca2+ release from sarcoplasmic reticulum (SR) vesicles. They are known to specifically oxidize free SH sites via a thiol-disulfide exchange reaction with the stoichiometric production of thiopyridone. Thus, the formation of a mixed S-S bond between an accessible SH site on an SR protein and a RDS causes large increases in SR Ca2+ permeability. Reducing agents, glutathione (GSH) or dithiothreitol reverse the effect of RDSs and permit rapid re-uptake of Ca2+ by the Ca2+, Mg2+-ATPase. The RDSs, 2,2'-DTDP, 4,4'-dithiodipyridine and SPDP displaced [3H]ryanodine binding to the Ca2+-receptor complex at IC50 values of 7.5 +/- 0.2, 1.5 +/- 0.1, and 15.4 +/- 0.1 microM, respectively. RDSs did not alter the rapid initial phase of Ca2+ uptake by the pump, stimulated ATPase activity, and induced release from passively loaded vesicles with nonactivated pumps; thus they act at a Ca2+ release channel and not at the Ca2+, Mg2+-ATPase. Efflux rates increased in 0.25-1.0 mM [Mg2+]free then decreased in 2-5 mM [Mg2+]free. Adenine nucleotides inhibited the oxidation of SHs on SR protein by RDSs and thus reduced Ca2+ efflux rates. However, once RDSs oxidized these SH sites and opened the Ca2+ release pathway, subsequent additions of nucleotides stimulated Ca2+ efflux. In skinned fibers, 2,2'-dithiodipyridine elicited rapid twitches which were blocked by ruthenium red. These results indicate that RDSs trigger Ca2+ release from SR by oxidizing a critical SH group, and thus provide a method to covalently label the protein(s) involved in causing these changes in Ca2+ permeability.
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PMID:Reactive disulfides trigger Ca2+ release from sarcoplasmic reticulum via an oxidation reaction. 253 12

Hypocrellin A (HA)-sensitized photoinactivation of enzymes in human erythrocyte membrane, including AchE, GPDH, Na(+)-K+ ATPase, Ca2(+)-Mg2+ ATPase were studied in this paper. The sensitivity of these four enzymes inactivated by HA and light are as following order: Ca2(+)-Mg2+ ATPase greater than Na(+)-K+ ATPase greater than GPDH greater than AchE. The relationship among ATPase inactivation, sulfhydryl photoinactivation and lipid peroxidation was also investigated. Results show that SH group photooxidation probably is one of the major reasons of enzyme inactivation whereas lipid peroxidation has little effect. The isolated GPDH was less sensitive than that membrane-bound, GSH, NAD acted protectively on GPDH and ATPase respectively. The evidence of electrophoresis and protein intrinsic fluorescence showed that protein structure did not change significantly even though most activity had lost in case of GPDH.
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PMID:[The study on hypocrellin A-sensitized photoinactivation of enzymes of human erythrocyte membranes]. 253 19

(Na+,K+)ATPase activity of rat liver plasma membranes was evaluated in female rats feeding an ethanol containing diet for 46 days (total ethanol ingested, 59.7 g/100 g body wt). Determinations were performed at the end of ethanol treatment or at various times after stopping treatment. (Na+,K+)ATPase and 5'-nucleotidase activities exhibited a 8- and 1.4-fold decrease, respectively, at the end of ethanol ingestion. In contrast no modifications of Mg2+-ATPase activity were observed. There also occurred, in ethanol-treated rats, release of sorbitol dehydrogenase into the blood, fat accumulation in liver cells, and decrease in reduced glutathione (GSH) liver content. A decrease in (Na+,K+)ATPase activity was also found in plasma membranes isolated from hepatocyte suspensions after a 2-hr incubation with 50 mM ethanol or 1 mM acetaldehyde (ACA), in conditions that caused a great fall in hepatocyte GSH content but did not cause cell death. After the cessation of ethanol administration, there occurred a progressive recovery of (Na+,K+)ATPase activity, GSH and triacylglycerol content, and release of sorbitol dehydrogenase. These parameters reached control values 12 hr after ethanol withdrawal. S-Adenosyl-L-methionine (SAM), L-methionine, and N-acetylcysteine (NAC), given to rats during ethanol treatment, prevented the decrease in (Na+,K+)ATPase activity and GSH content. They also reduced steatosis and liver necrosis. The efficiency of these compounds decreased in this order: SAM, methionine, NAC. SAM accelerated the recovery of all parameters studied after ethanol withdrawal, and also protected (Na+,K+)ATPase activity and GSH content of isolated hepatocytes from the deleterious effect of ethanol. These SAM effects were prevented by 1-chloro-2,4-dinitro-benzene, a compound which depletes cell GSH. Treatment of isolated hepatocytes with [35S]SAM led to the synthesis of labeled GSH. The total amount and specific activity of labeled GSH underwent a significant increase, in the presence of 2 mM ethanol or 0.5 mM ACA, which indicates a marked stimulation of GSH synthesis by ethanol and ACA. These data indicate that ethanol intoxication may inhibit (Na+,K+)ATPase activity; an effect that does not seem to depend on cell necrosis. SAM, methionine, and NAC exert various degrees of protection toward ethanol-induced cell injury, which are related to the efficiency of these compounds in maintaining a high GSH pool.
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PMID:Inhibition by ethanol of rat liver plasma membrane (Na+,K+)ATPase: protective effect of S-adenosyl-L-methionine, L-methionine, and N-acetylcysteine. 253 5

We investigated the interaction of triethyllead with ATP-coupled cellular enzymatic activities and the role of GSH to reverse the observed inhibition of these enzymes. Triethyllead inhibited the membrane bound Na+-K+-ATPase from HeLa cells (IC50 12 microM) and the ATP-hydrolysing activity of the mitochondrial F0-F1-ATPase complex (IC50 17 microM). Addition of 1 mM GSH reversed both enzyme activities totally, whereas lower GSH concentrations showed a less pronounced effect. Surprisingly, in freshly isolated rat liver mitochondria the ATP-synthesizing activity was also inhibited by triethyllead (IC50 16 microM), in spite of a measured high intramitochondrial GSH concentration (up to 10 mM). Further experiments in isolated submitochondrial particles revealed that ATP-synthesis and ATP-hydrolysis were inhibited by triethyllead with similar IC50 values, and both activities could be protected in vitro from the organolead compound in the presence of 1 mM GSH. Thus in all activities tested in vitro a high excess of GSH over triethyllead (greater than or equal to 25-fold) is necessary to restore the inhibited enzymes. The intramitochondrial triethyllead concentration was further determined after incubation of intact mitochondria with 10 microM of the organolead compound. The organolead concentration measured was as high as 600 microM. This means that in intact mitochondria there exists only a ca. 16-fold excess of GSH, which has been shown to be insufficient to protect ATP-synthesizing and ATP-hydrolyzing activities of the F0-F1-ATPase from triethyllead in vitro. We concluded that in intact mitochondria the F0-F1-ATPase complex is inhibited by triethyllead due to its accumulation in the matrix.
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PMID:Inhibition of cellular activities by triethyllead. Role of glutathione and accumulation of triethyllead in vitro. 255 37

Methemoglobin formation and reduction in canine erythrocytes with inherited high Na,K-ATPase activity (HK cells) were compared with those in normal canine cells (LK cells). Nitrite-induced methemoglobin formation in hemoglobin solutions indicated that the hemoglobin from HK cells was oxidized at essentially the same rate as that of LK cells. However, methemoglobin formation in HK cells was slower due to the inhibition by high glutathione (GSH) concentration. Methemoglobin reduction was allowed to take place on nitrite-treated and washed erythrocytes in a glucose medium and was reduced more rapidly in HK cells than in LK cells. During the reduction, the amounts of lactate and pyruvate increased more rapidly in HK cells, indicating enhanced glycolysis in HK cells. It is thus evident that the hemoglobin of HK cells is more securely protected from nitrite-induced oxidation by the GSH presence in great excess and by the increase in glycolysis.
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PMID:Methemoglobin formation and reduction in canine erythrocytes with inherited high Na,K-ATPase activity. 255 75


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