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)

During a stimulus train, the diastolic membrane potential of rat atria exhibits a depolarization phase followed by a slower repolarization phase which has been attributed to the activation of an electrogenic sodium pump (ATPase Na+, K+). This pump seems to be all the more active as stimulation frequency is higher. The parallel evolution of the sodium pump inhibition and a positive inotropic effect in response to ouabain perfusion, suggests that the enzymatic inhibition is directly involved in the development of the cardiotonic effect of digitalis.
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PMID:[Correlation between inhibition of stimulatory membrane repolarization and positive inotropic response caused by ouabain in rat heart]. 40 24

Intravenous infusion of acetylstrophanthidin to 6 dogs, after a 60 min left anterior descending coronary artery occlusion, was associated with a 43.0 +/- 10.5% decrease in the dose of digitalis needed to produce ventricular arrhythmias as compared to the pre-ischemic dose (97.5 +/- 8.0 microgram/kg). Reperfusion of the ischemic region for 2 h after a 90 min occlusion resulted in a 54.4 +/- 6.7% decrease in the arrhythmogenic dose. Direct intracoronary infusions of digitalis into the ischemic region, after a 90 min coronary occlusion followed by 2 h of reperfusion, was associated with a 47.7 +/- 6.4% decrease in the dose of digitalis needed to produce arrhythmias. The pre-ischemic (control) arrhythmogenic dose of digitalis via the intracoronary infusion method was 1.5 +/- 0.3 microgram/kg (mean +/- S.E.M. of 7 dogs). Sodium pump activity, estimated from the ouabain-sensitive 86Rb uptake in sodium-loaded ventricular slices, was significantly higher in slices obtained from the ischemic regions (6.84 +/- 0.30 nmoles 86Rb/mg dry wt. (mean +/- S.E.M.), than from the non-ischemic regions (3.43 +/- 0.64 nmoles 86Rb/mg dry wt.). Sensitivity of the sodium pump activity to the inhibitory effect of ouabain also was increased in the ischemic regions as indicated by a shift in the log dose--response curve to the left. Thus, it appears that there is an increase in myocardial sensitivity to the toxic effect of digitalis after temporary ischemia and it appears to be related to an increase in the sensitivity of the Na+,K+-ATPase or sodium pump to the inhibitory effect of digitalis.
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PMID:Ischemic-induced alterations in cardiac sensitivity to digitalis. 48 58

1. We have developed a procedure for preparing resealed red cell ghosts that contain ADP but very little ATP. 2. The procedure involves (i) lysis of the cells in a very large volume of lysing solution, (ii) resuspension of the ghosts in a small volume, (iii) the incorporation into the ghosts, before they are resealed, of the adenylate kinase inhibitor P1,P5-di(adenosine-5'-)pentaphosphate (AP5A) and of hexokinase, and (iv) the removal of traces of ATP, formed by residual adenylate kinase activity, by the addition of glucose. 3. Measurements of sodium efflux from ghosts prepared in this way show that sodium-sodium exchange through the sodium pump does not occur in the absence of ATP even if ADP is present. 4. The beta:gamma imido analogue of ATP (AMP.PNP), which is incapable of phosphorylating sodium, potassium-ATPase, cannot replace ATP in supporting sodium-sodium exchange. 5. These findings support the hypothesis that the outward movement of sodium ions through the sodium pump is associated with the transfer of a phosphoryl group from ATP to the enzyme, and that the inward movement of sodium ions through the pump is associated with the return of a phosphoryl group from the phosphoenzyme to ADP.
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PMID:Sodium-sodium exchange through the sodium pump: the roles of ATP and ADP. 53 26

Ouabain (10(-7) to 10(-4) M) elicited concentration-dependent contractile responses in human placental arteries. The contractions were reduced by 10(-4) M amiloride and Ca(2+)-free medium, but not affected by 10(-6) M nifedipine or 10(-6) M Bay-K-8644, which markedly reduced or potentiated 75 nM K(+)-induced contractions, respectively. After contracting the vessels with 10(-6) M prostaglandin F2 alpha in a K(+)-free medium, the subsequent addition of 7.5 mM K+ induced a marked relaxation, which was blocked by 10(-6) M ouabain. This glycoside (10(-8) to 10(-4) M) also produced a concentration-dependent reduction of 86Rb+ uptake. Scatchard analysis of the [3H]-ouabain binding to membrane fractions from human placental arteries suggests a single class of binding sites with a KD of 88.3 nM and a Bmax of 345 fmol/mg. 5-Hydroxytryptamine (5-HT; 10(-9) to 10(-5) M) caused concentration-dependent contractions. Single concentrations produced transient responses composed of an initial contraction, followed by a slow fall in tension. Ouabain (10(-8) to 10(-6) M), K(+)-free medium or the reduction of bath temperature (28 degrees C) did not modify contractions but inhibited the relaxant phase of the response. 5-HT (10(-8) to 10(-6) M) increased both total and ouabain-insensitive 86Rb+ uptake, but the difference between them was not modified. These data indicate that: (1) human placental arteries possess an important sodium pump activity, inhibition or stimulation of which markedly alters vascular tone, (2) ouabain-evoked contractions are produced by Ca2+ entry mainly through Na(+)-Ca2+ exchange, secondary to intracellular Na+ accumulation, (3) the relaxant component of 5-HT response is dependent on the activity of the sodium pump, (4) the activation of Na+,K(+)-ATPase activity by this amine is not apparently due to direct effect, and (5) the inhibition of the sodium pump can cause long lasting increases of placental vascular resistance in the presence of physiological concentrations of 5-HT.
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PMID:Functional role of sodium pump in human placental arteries. 131 25

Using polyethylene glycol-mediated fusion of ATP-ase-enriched (native) microsomes with red blood cells, we have delivered sarcoplasmic reticulum (SR) Ca-ATPase and kidney Na,K-ATPase into the mammalian erythrocyte membrane. Experiments involving delivery of the SR Ca-ATPase into human red cells were first carried out to assess the feasibility of the fusion protocol. Whereas there was little detectable 45Ca2+ uptake into control cells in either the absence or presence of extracellular ATP, a marked time-dependent uptake of 45Ca2+ was observed in the presence of ATP in cells fused with SR Ca-ATPase. Comparison of the kinetics of uptake into microsome-fused cells versus native SR vesicles supports the conclusion of true delivery of pumps into the red cell membrane. Thus, the time to reach steady state was more than two orders of magnitude longer in the (large) cells versus the native SR vesicles. Na,K-ATPase from dog and rat kidney microsomes were fused with red cells of humans, sheep, and dogs. Using dog kidney microsomes fused with dog red cells which are practically devoid of Na,K-ATPase, functional incorporation of sodium pumps was evidenced in ouabain-sensitive Rb+ uptake and Na+ efflux energized by intracellular ATP, as well as in ATP-stimulated Na+ influx and Rb+ efflux from inside-out membrane vesicles prepared from the fusion-treated cells. From analysis of the biphasic kinetics of ouabain-sensitive Na+ efflux under conditions of limited intracellular Na+ concentration, it is concluded that the kidney pumps are incorporated into a relatively small fraction (approximately 15%) of the red cells. This system provides a uniquely useful system for studying the behavior of native sodium pumps in a compartment (red cell) of small surface/volume ratio. The newly incorporated native kidney pumps, while of the same isoform as the endogenous red cell pump, behave differently from the endogenous red cell sodium pump with respect to their very low "uncoupled" Na+/O flux activity.
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PMID:Delivery of ion pumps from exogenous membrane-rich sources into mammalian red blood cells. 131 86

Recently, a beta subunit for the rat gastric H+,K(+)-ATPase (HK beta), which is structurally similar to the beta subunit of Na+, K(+)-ATPase, has been cloned and characterized. Using heterologous expression in yeast, we have tested the specificity of beta subunit assembly with different isoforms of the alpha subunit of Na+, K(+)-ATPase. Coexpression in yeast cells of the HK beta with both the sheep alpha 1 subunit and the rat alpha 3 subunit isoforms of Na+, K(+)-ATPase (alpha 1 and alpha 3, respectively) leads to the appearance of high-affinity ouabain-binding sites in yeast membranes. These ouabain-binding sites (alpha 1 plus HK beta, alpha 3 plus HK beta) have a high affinity for ouabain (Kd, 5-10 nM) and are expressed at levels similar to those formed with the rat beta 1 subunit of Na+, K(+)-ATPase (beta 1) (alpha 1 plus beta 1 or alpha 3 plus beta 1). Potassium acts as a specific antagonist of ouabain binding by alpha 1 plus HK beta and alpha 3 plus HK beta just like sodium pumps formed with beta 1. Sodium pumps formed with the HK beta, however, show quantitative differences in their affinity for ouabain and in the antagonism of K+ for ouabain binding. These data suggest that the structure of the beta subunit may play a role in sodium pump function.
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PMID:High-affinity ouabain binding by yeast cells expressing Na+, K(+)-ATPase alpha subunits and the gastric H+, K(+)-ATPase beta subunit. 131 69

To investigate the participation of the pineal gland and its hormone melatonin on Na(+)-K(+)-ATPase (the sodium pump) in rat brain, we used Scatchard plots to analyze the changes in rat cerebral cortex of [3H]ouabain high-affinity binding in groups of intact, pinealectomized (PX), and sham-PX rats. Only one type of binding site, with a dissociation constant of approximately 3 nM and site number (Bmax) of approximately 250 fmol/mg protein, was apparent with our assay conditions. PX or sham-PX rats (subjected to surgery 15 days earlier) were killed at six different time intervals during the 24-h cycle. Intact and sham-PX animals showed a similar biphasic pattern in diurnal rhythm of ouabain binding, with a minimal concentration of binding sites at 1600 h and a maximal concentration at 0400 h. Pinealectomy induced a significant increase in Bmax at all time intervals studied, with the largest rise appearing at night and coinciding with the nocturnal peak, whereas the daytime minimum was blunted. Time-dependent experiments indicated that the Bmax of ouabain high-affinity binding in PX rats attained maximal values at 7 days after surgery and decreased somewhat 7 days later, while sham-PX animals showed only a small transient increase in Bmax up to 7 days after surgery, with values returning to normal by the 15th day. Melatonin administration at a single subcutaneous dose of 25 micrograms/kg body wt given 3 h before death was enough to counteract the PX-induced increase of ouabain high-affinity binding. Melatonin was able to enhance the binding of [3H]ouabain to its receptor site, increasing binding affinity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation by pineal gland of ouabain high-affinity binding sites in rat cerebral cortex. 131 17

Cystinosis is an inherited metabolic disease characterized by accumulation of lysosomal cystine and renal impairment. In an attempt to better understand the link between cystine accumulation and renal functions, we studied the effects of cystine loading on the Na(+)-H+ antiporter and the sodium pump in renal epithelial cells (LLC-PK1) in culture. Incubation of LLC-PK1 with 1 mM cystine dimethyl ester (CDME) for 48 h caused lysosomal cystine loading and reduced by 22 +/- 2% the maximal velocity of sodium-hydrogen antiport with no significant change in the affinity of sodium for the transporter. Rubidium influx decreased to 46 +/- 5% of control. Ouabain binding experiments revealed a 10% reduction in the number of Na(+)-K(+)-ATPase units in the intact cells. Na(+)-K(+)-ATPase activity in the particulate fraction of the cells homogenate declined to 50 +/- 7.5% of controls. No significant change was observed in the activity of ouabain-insensitive phosphatases. The intracellular concentration of sodium increased from 20.6 +/- 3.7 to 64.8 +/- 10 mM, and potassium concentration decreased from 103 +/- 6 to 80 +/- 13 mM. In addition to the observed reduction in the sodium gradient and in agreement with the reduction in the intracellular potassium concentration, the membrane potential changed from -80.8 +/- 7.5 to -69.9 +/- 7.0 mV. The results suggest that intracellular accumulation of cystine is associated with reduction in the number and the activity of membrane transporters. The consequence of the changes in the activity of Na(+)-K(+)-ATPase is a reduction in the electrochemical forces that drive transport in the renal cells tested.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cystine dimethyl ester reduces the forces driving sodium-dependent transport in LLC-PK1 cells. 132 21

The Na+,K(+)-ATPase ion pump plays a critical role in fluid and electrolyte physiology of the small intestine. Here we show that, of the three known alpha isotypes (alpha 1, alpha 2, and alpha 3) of the sodium pump found in the rat, only alpha 1 is expressed in the small intestine. The expression of this isotype, considered at the level of mRNA, is under developmental control, with the adult intestine exhibiting approximately a threefold increase in alpha 1 message over the neonate. Cortisone treatment of the neonate results in near-adult levels of alpha 1 mRNA expression. An increase in the abundance of alpha 1 isotype parallels the changes in its mRNA expression. beta subunit mRNA is expressed coordinately with the alpha 1 subunit mRNA. A four- to five-fold rise in the Na+,K(+)-ATPase activity is also developmentally induced.
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PMID:Expression and developmental regulation of Na+,K+ adenosine triphosphatase in the rat small intestine. 132 91

The effects of diltiazem, verapamil, bepridil, nicardipine and nifedipine were studied in vitro on Na+,K(+)-ATPase from dog kidney (EC 3.6.1.37). Except diltiazem, all the drugs tested showed an inhibitory effect on Na+,K(+)-ATPase activity in a dose-dependent manner. Among these drugs bepridil is far more effective than the others (IC50 approximately 10(-4) M). Competition studies showed that bepridil acted in a non-competitive manner with the ATP-Mg2+ complex and in a partially competitive manner with K+. Since ouabain acted similarly under the same experimental conditions, we tested the interaction of bepridil and ouabain on Na+,K(+)-ATPase. With low doses of ouabain, the enzyme inhibition corresponded to a potentiated synergy of the two drugs. We then studied the action of bepridil on the sodium pump activity of intact red blood cells by an ex vivo microcalorimetric technique. At 10(-5) M bepridil caused a significant decrease in sodium pump activity (33 +/- 8%).
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PMID:Inhibition of sodium pump by bepridil. An in vitro and microcalorimetric study. 132 68


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