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PubMed1993

The role of the sodium pump and sodium-calcium exchange in recovery from calcium overload in guinea-pig ventricular myocytes.

A marked increase in [Ca2+]i is provoked in isolated guinea-pig ventricular myocytes by return to normal Tyrode solution after a period of exposure to fluid free of divalent cations. When the sarcolemma of the myocyte remains intact, [Ca2+]i falls back towards initial levels over the next 5 to 10 min in spite of the strong irreversible contracture. This recovery fails to occur if either the Na+ pump or Na(+)-Ca2+ exchange is inhibited once [Ca2+]i has risen.

Animals↗
PubMed1982

Sodium channel, sodium pump, and sodium-calcium exchange activities in synaptosomal plasma membrane vesicles.

Two mechanisms of Na+ influx have been observed using synaptosomal plasma membrane vesicles purified by density gradient centrifugation from a synaptosomal hypotonic lysate. First, a 5-fold increase in uptake over basal Na+ entry occurs with 50 microM veratridine. The veratridine-dependent Na+ uptake is partially inhibited by 2 microM tetrodotoxin with an apparent time dependency of action (half-maximal inhibition in approximately 20 min). Second, a larger Na+ accumulation (approximately 15-fold above basal) was observed with 2.5 mM ATP, this effect being dependent on internal K+ loading of vesicles although inhibited by high external K+. The two uptake processes are believed to represent operation of the plasma membrane voltage-sensitive Na+ channel, and the Na+-pumping (Na+ + K+)-ATPase, respectively. Both Na+ flux mechanisms appear to operate in a single population of vesicles since opening of the Na+ channel with veratridine diminishes the ATP-dependent accumulation of Na+ by over 75%. An inverted orientation of the plasma membrane vesicles is likely to account for the functioning of the ATP-dependent Na+ pump and may also account for the low sensitivity and time dependency of the inhibitory action of tetrodotoxin on Na+ channel-opening. Na+ accumulated by the Na+ pump was rapidly effluxed by 10 mM external Ca2+ via the Na+-Ca2+ exchange mechanism which (together with an ATP-dependent Ca2+-accumulating mechanism) was recently characterized in the vesicles (Gill, D. L., Grollman, E. F., and Kohn L. D. (1981) J. Biol. Chem. 256, 184-192). This result, together with the observed inhibition of Ca2+ influx via (Na+-Ca2+)-exchange due to veratridine-mediated Na+ flux, strongly suggests that the Na+ pump, Na+ channel, and both Ca2+ transport mechanisms function in a single population of inverted plasma membrane vesicles.

Animals↗
PubMed1987

[3H]noradrenaline release from rabbit pulmonary artery: sodium-pump-dependent sodium-calcium exchange.

1. The release of [3H]noradrenaline ([3H]NA) from the isolated main pulmonary artery of the rabbit has been measured in the presence of neuronal (cocaine, 3 X 10(-5) M) and extraneuronal (corticosterone, 5 X 10(-5) M) uptake blockers. 2. K+ removal from the external medium increased the release of [3H]NA, an action transiently inhibited by Ca2+-free (+1 mM-EGTA) solution, i.e. after Ca2+ removal transmitter release was first abolished and then started to increase again after a delay lasting about 90-120 min. 3. Ca2+ readmission to arteries which had been kept in Ca2+- and 'K+-free' solution, markedly increased the [3H]NA release. The rate of transmitter release was dependent on the preceding perfusion period with 'K+-free' solution, being greater for longer exposure times. 4. When Ca2+ and K+ were readmitted together to K+-depleted and Na+-enriched preparations, the release of [3H]NA transiently increased. 5. If K+ was readmitted first, the subsequently applied Ca2+ was ineffective in producing transmitter release. 6. Different alkali metal ions (Rb+, Cs+ or Li+) were also readmitted as K+ substitutes together with Ca2+. In all cases the release of neurotransmitter transiently increased; however, the rate of release was dependent on the monovalent cation used. Thus, Rb+ ions were as effective as, Cs+ about one-third as effective as, and Li+ about one-fifth as effective as K+ in activating the Na+ pump. 7. It is concluded that in the absence of external Ca2+, and in response to Na+-pump inhibition, the release of Ca2+ from internal stores is responsible for the NA release observed. On readmission of Ca2+ the rate of transmitter release is dependent on the Na+ previously gained inside. Furthermore, the activity of the Na+ pump determines the rate of transmitter release through the Na-Ca exchange mechanism.

Animals↗
PubMed1967

The sensitivity of the sodium pump to external sodium.

1. When red cells are incubated in potassium-free solutions, ouabain-sensitive sodium efflux is nearly absent with 5 mM-Na externally, but increases as the external sodium concentration is reduced from 5 mM to zero. This increase suggests that the transport mechanism is very sensitive to small amounts of sodium at the outside surface of the cell membrane. Further evidence for such sensitivity has been obtained from the effects of external sodium on the relation between potassium influx and external potassium concentration.2. With 5 mM-[K](o), potassium influx is rather insensitive to [Na](o) but at low potassium concentrations even low levels of sodium inhibit.3. With 140 mM-[Na](o) the potassium influx curve is S-shaped below 1 mM [K](o). At much lower sodium concentrations, the S-shaped region and the value of [K](o) for which potassium influx is half-maximal are both shifted progressively towards zero. At 10 muM-[Na](o), potassium influx is half maximal at 0.14 mM-[K](o) and the curve is close to a rectangular hyperbola down to 22 muM-[K](o); there seems to be a trace of inflexion at about 15 muM-[K](o).4. When [Na](o) is reduced from 5 mM to zero, removal of the inhibitory effect of external sodium ions on sodium: potassium exchange could lead to an increase in sodium efflux into nominally potassium-free solutions if these solutions did in fact contain traces of potassium. Such traces could arise by leakage from the cells, but, in a number of experiments, direct measurements showed that [K](o) was too low to account in this way for all of the observed ouabain-sensitive sodium efflux. A further reason for rejecting this explanation is that ouabain-sensitive potassium loss into nominally (Na+K)-free solutions was unaffected by adding 5 mM-Na. (A slight increase in ouabain-resistant loss was observed.)5. The ouabain-sensitive efflux of sodium into (Na+K)-free solutions therefore seems to represent a mode of behaviour of the transport mechanism distinct both from the sodium: potassium exchange that occurs under physiological conditions and from the sodium: sodium exchange that occurs in K-free, Na-rich media.

Biological Transport↗
PubMed1991

The effects of cholesterol depletion on the sodium pump in human red cells.

Sodium pump function has been studied in human erythrocytes depleted of membrane cholesterol by incubation with phosphatidylcholine liposomes. The cells were sodium loaded by incubation in alkaline sodium phosphate and sodium pump activity was assessed by measurements of ouabain-sensitive 86Rb uptake at 37 degrees C. Cholesterol depletion had a biphasic effect; depletion by 5-25% increased sodium pump activity by a mean of 16.1% (S.D. 3.2%), whereas depletion by 35-50% decreased sodium pump activity by a mean of 14.8% (S.D. 3.8%). Cholesterol depletion had no reproducible effect on the ouabain-insensitive uptake of Rb. These results support the hypothesis that there may be an optimum membrane cholesterol content for sodium pump function.

Biological Transport, Active↗
PubMed1991

Up-regulation of sodium pump activity in Xenopus laevis oocytes by expression of heterologous beta 1 subunits of the sodium pump.

Recent evidence suggests that the beta subunit of the Na+ pump is essential for the alpha subunit to express catalytic activity and for assembly of the holoenzyme in the plasma membrane. We report here that injection into Xenopus laevis oocytes of cRNAs specific for beta 1 subunit isoforms of the Na+ pump of four species (Torpedo californica, chicken, mouse and rat) causes a time-dependent increase in the number of ouabain-binding sites, both in the plasma membrane and in internal membranes. Expression of the beta 1 subunit of the Na+ pump of mouse and rat in the oocytes could be substantiated by immunoprecipitation using a polyclonal antiserum against the mouse beta 1 subunit. Scatchard analysis in permeabilized cells disclosed that the affinity for ouabain is unchanged after expression of each of the beta 1 subunits. A proportional increase in ouabain-sensitive 86Rb+ uptake indicates that the additionally expressed ouabain-binding sites on the cell surface represent functional Na+ pumps. The findings support the concept of Geering. Theulaz, Verrey, Häuptle & Rossier [(1989) Am. J. Physiol. 257, C851-C858] that beta 1 subunits expressed in oocytes associate with an excess of endogenous alpha subunits of the Na+ pump to form a hybrid enzyme. In addition, all of the beta 1 isoforms investigated in the present study were also capable of combining with the co-expressed alpha 1 subunit of the Torpedo Na+ pump to produce a functional enzyme. Injection of cRNA encoding for the Torpedo alpha 1 subunit alone had no effect on the ouabain-binding capacity of the surface and intracellular membranes of the oocyte.

Animals↗
PubMed2002

The cardiac sodium pump: structure and function.

Cardiac sodium pumps (Na,K-ATPase) influence cell calcium and contractility by generating the Na+ gradient driving Ca++ extrusion via the Na+/Ca++ exchanger (NCX), and are the receptors for cardiac glycosides such as digitalis which increases cardiac contractility by decreasing the Na+ gradient driving Ca++ extrusion. There are multiple isoforms of the sodium pump expressed in the heart indicating the potential for isoform specific expression patterns, function and regulation. Regarding isoform expression patterns, human heart expresses alpha1, alpha2, alpha3, beta1 and a small amount of beta2. Within the human heart, alpha3, beta1 and NCX levels are 30-50% lower in atria than ventricles, associated with increased sensitivity to inotropic stimulation. Distribution at the cellular level has been studied in the rat heart where both alpha1 and alpha2 are detected in the T-tubules along with NCX. Regarding isoform function, we focussed on human sodium pumps as cardiac glycoside receptors. A study of human sodium pump expressed alone (alpha1) or in combination (alpha1 with alpha2, or alpha1 with alpha2 and alpha3) in their native membranes aimed to determine whether different isoforms had distinct affinities for the cardiac glycoside ouabain by evaluating whether the ouabain binding data were best fit with a single site or two site model. The results indicated that the affinity of these human a subunit isoforms for ouabain is indistinguishable, and that changes in sensitivity to cardiac glycosides during heart failure are likely due to a decrease in the total number of pumps rather than a shift in expression to a more sensitive isoform. Regarding isoform regulation, we hypothesized that a primary decrease in cardiac Na,K-ATPase expression would be associated with a secondary increase in cardiac Na+/Ca++ exchanger expression as a homeostatic mechanism to blunt an increase in cell Ca++ stores (and visa versa with an increase in Na,K-ATPase). Supporting the hypothesis: in a rat model of renovascular hypertension, or after treatment with amiodarone there are 50% decreases in alpha2 levels with 35-40% increases in NCX levels in left ventricle, while in the transition from hypo- to hyperthyroid, there are increases in both alpha1 (2-fold) and alpha2 (8-fold) with decreases in NCX (0.45-fold). In comparison, in transgenic mice overexpressing NCX, there was no secondary change in Na,K-ATPase alpha1 or alpha2 levels indicating that primary changes in NCX do not drive secondary changes in Na,K-ATPase in the heart. This information provides the basis for addressing the significant gaps in our understanding of the physiologic, structural and homeostatic coupling between sodium pump isoforms and Na+/Ca++ exchangers in the heart and how coupling is related to control of cardiac contractility in health and disease.

Animals↗
PubMed1984

Autoregulation of the electrogenic sodium pump.

The dependence of electrogenic sodium pump activity on changes in the cell volume of Helix pomatia neurons with different levels of intracellular sodium ion concentration was studied. Hypertonic solutions caused hyperpolarization of the membrane and increased membrane resistance in cells with a low sodium content (low-sodium cells; LSC). The activity of the electrogenic sodium pump in hypertonic solutions was increased compared to the activity in hypotonic solutions in LSC and decreased in cells with a high sodium content (high-sodium cells; HSC). The concentration of ouabain which led to maximal inhibition of active 22Na efflux from the neurons was 10(-4) M. Lower concentrations of ouabain (10(-8) M and lower) did not inhibit the sodium pump but stimulated it. The swelling of neurons in hypotonic solutions was accompanied by an increase in the number of binding sites for ouabain, while shrinking in hypertonic solutions led to the opposite effect--a decrease in binding sites. An increase in the number of binding sites also took place in normal isotonic potassium-free solutions compared with normal Ringer's solution. Two saturable components of ouabain binding were detectable in all solutions examined. gamma-Aminobutyric acid (GABA) and acetylcholine (ACh) increased the number of ouabain binding sites on the membrane. The results suggest that there are two opposite mechanisms by which cell volume changes can modulate the pump activity. One of them depends on the intracellular sodium ion concentration and causes pump activation in hypertonic solutions in LSC and saturation in HSC, while a second mechanism mediates the activating effect of cell swelling on the sodium pump in HSC. In addition, there may be a negative feedback between the pump activity and the number of functioning pump units in the membrane.

Adenosine Triphosphatases↗
PubMed1984

The dual effect of sodium ion on the digitalis-sodium pump interaction.

Digitalis glycosides are specific inhibitors of the sodium pump. While their effects on isolated Na,K-ATPase, an enzymatic representation of the sodium pump, can be quantified easily and precisely, estimation of their effects on the sodium pump and evaluation of the physiological significance of sodium pump inhibition are complicated by several factors. In isolated Na,K-ATPase, the specific binding of cardiac glycosides observed in the presence of Mg2+ and ATP is stimulated by Na+. In intact myocardial cells, conditions which enhance Na+ influx, and hence the amount of Na+ to be transported by the sodium pump, such as stimulation at high frequencies, presence of monensin (a sodium ionophore), batrachotoxin or grayanotoxin I, enhance the glycoside binding to the sodium pump. In left atrial muscle preparations isolated from the guinea-pig heart and stimulated at 0.5 Hz, binding of ouabain to glycoside binding sites on Na,K-ATPase was eliminated by lowering the extracellular Na+ concentration from 145 to 27 mM, a condition reported to lower the intracellular Na+ concentration by more than 60%. When ouabain exposure of atrial muscle preparations was restricted to the quiescent period, glycoside binding to the sodium pump was minimal. Monensin, however, caused ouabain to bind to the sodium pump in quiescent preparations. These results indicate that glycoside binding to the sodium pump is enhanced by intracellular Na+. In addition to enhancing the glycoside binding to the sodium pump, an elevation of intracellular Na+ reduces the reserve capacity of the sodium pump and therefore increases the sensitivity of the myocardium to sodium pump inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Cardiotonic steroids: potential endogenous sodium pump ligands with diverse function.

The highly conserved cardiotonic steroid (CS) binding site present on the ubiquitous membrane sodium pump, sodium, potassium-ATPase, appears to have been conserved by no force other than its capacity to bind CS: a family that includes plant-derived cardiac glycosides and putative endogenous vertebrate counterparts. Binding of ligand is inhibited by increased extracellular potassium. This implies functional coordination because inhibition of the sodium pump would be counterproductive when extracellular potassium is elevated. The interesting biology of the CS binding site continues to stimulate investigations into the identity of endogenous ligands, their role as pump regulators at the cellular level, and as mediators of body fluid balance and blood pressure regulation. In addition to inhibition of sodium and potassium transport, there is considerable recent evidence suggesting that the sodium pump may act as a cell signaling receptor activated by CS binding and responding by coordination of intracellular signaling pathways that can be dependent on and also independent of the reduction in transmembrane ion flux resulting directly from pump inhibition. This signaling may influence cell survival, growth, and differentiation. Recent insight into the biology of pump regulation by CS is reviewed.

Adrenal Cortex↗
PubMed1988

Arsenate substitutes for phosphate in the human red cell sodium pump and anion exchanger.

The sodium pump of human red blood cells mediates a Rb:Rb exchange that is dependent for maximal rates upon the simultaneous presence of intracellular ATP (or ADP) and phosphate. We have measured ouabain-sensitive 86Rb uptake into resealed ghosts of human red cells containing ADP and show that arsenate will substitute for phosphate in supporting the Rb:Rb exchange transport mode. The concentration dependence of arsenate-supported Rb:Rb exchange in ghosts containing 2 mM ADP shows both activating and inhibiting phases; the dependence upon phosphate shows similar characteristics. Elevation of the external [Rb] lowers the apparent affinity for arsenate since there is a shift to higher concentrations of arsenate in the activating and inhibiting phases of the arsenate concentration dependence curve. Similarly, elevation of [ADP] substantially reduces the inhibition of Rb:Rb exchange observed at higher [arsenate]. These effects are also observed in phosphate-supported Rb:Rb exchange. The phosphate requirement for Rb:Rb exchange involves phosphorylation of the sodium pump protein; the close agreement between the effects of arsenate and phosphate in supporting Rb:Rb exchange makes it likely that arsenylation of the sodium pump occurs during Rb:Rb exchange. Arsenate efflux from red blood cell ghosts into arsenate-free chloride medium is partially inhibited (77-80%) by DNDS (4,4'-dinitro-2,2'-stilbenedisulfonic acid), this compares with 82-87% inhibition by DNDS of phosphate efflux under the same conditions. It appears that Band III, the red cell anion transport system, accepts arsenate in a similar fashion to phosphate and that a fraction of the flux of both anions may occur through pathways other than Band III. Thus, in human red blood cells, both the sodium pump and the anion exchange transport system will accept arsenate as a phosphate congener and the protein-arsenate interactions are very similar to those with phosphate.

Arsenates↗
PubMed1997

Renal sodium pump regulation in deoxycorticosterone salt hypertension in the rat.

The renal sodium pump participates in sodium homeostasis and has been predicted to have a role in salt dependent forms of hypertension. However, the status of the renal sodium pump in volume-dependent hypertension is unclear. We assessed the renal sodium pump and its activity in the deoxycorticosterone acetate (DOCA)-salt model in rats, a model of volume-dependent hypertension. Sprague-Dawley rats on ad libitum diet were compared with four groups of litter mates receiving high or low salt diets, with or without DOCA administration. The renal sodium pump evaluation included measurement of hydrolytic activity, ouabain binding capacity and affinity, sodium activation, active pump units (determined by phosphoenzyme level), dephosphorylation rate, and isoform specific molecular expression. Intrinsic enzyme properties, including sodium and ouabain affinities, as well as turnover rate per sodium pump, were identical among the five groups. In contrast, the combination of DOCA and high salt intake (DOCA high salt) produced marked, significant increases in hydrolytic activity, ouabain binding capacity, phosphoenzyme level, and alpha1-isoform expression. DOCA low salt animals showed much smaller but significant increases in pump number. We conclude that DOCA and volume expansion may each alter renal sodium pump regulation, but volume expansion is clearly dominant. Increased renal sodium pump activity in DOCA high salt animals would, if unmitigated, favor sodium reabsorption and may contribute to hypertension.

Animals↗
PubMed1994

Palytoxin induces K+ efflux from yeast cells expressing the mammalian sodium pump.

Palytoxin causes potassium efflux and sodium influx in all investigated animals cells. Much evidence points to the sodium pump (Na+/K(+)-ATPase) as the target of the toxin. A heterologous expression system for mammalian Na+/K(+)-ATPase in the brewers yeast Saccharomyces cerevisiae has been used to test this hypothesis. Yeast cells do not contain endogenous sodium pumps but can be transformed with vectors coding for the alpha and beta subunits of the mammalian sodium pump. We now show that transformed yeast cells expressing both alpha and beta subunits of Na+/K(+)-ATPase are highly sensitive to the toxin, as measured by the loss of intracellular potassium. Palytoxin-induced potassium efflux is completely inhibited by 500 microM ouabain. In contrast, nontransformed yeast cells or cells expressing either the alpha or beta subunits are insensitive to palytoxin. Thus, the alpha/beta heterodimer of the sodium pump is required for the release of potassium induced by palytoxin. The results suggest that palytoxin converts the sodium pump into an open channel, allowing the passage of alkali ions.

Acrylamides↗
PubMed1970

Characteristics of electrogenic sodium pumping in rat myometrium.

Sodium-rich myometrium, obtained from the uteri of pregnant rats, rapidly hyperpolarized when 4.6-120 mM potassium was added to the bathing medium at 37 degrees C. Hyperpolarization was due to sodium pumping since the process was markedly temperature dependent, was abolished by ouabain, and required both intracellular sodium and extracellular potassium. The observed membrane potential exceeded the calculated potassium equilibrium potential during hyperpolarization providing evidence that sodium pumping was electrogenic. Hyperpolarization was reduced in the presence of chloride. The rate of sodium pumping may influence potassium permeability since potassium apparently did not short-circuit the pump during hyperpolarization.

Animals↗
PubMed1982

ATP-driven sodium pump in Streptococcus faecalis.

Sodium extrusion by bacteria is generally attributed to secondary antiport of Na+ for H+ energized by the proton circulation. Streptococcus faecalis is an exception, in that sodium expulsion from intact cells requires the generation of ATP but does not depend on the protonmotive force. Unfortunately, studies with everted membrane vesicles failed to reveal the expected sodium pump; instead, the vesicles contained a conventional secondary Na+/H+ antiporter. We report here that everted membrane vesicles prepared in the presence of protease inhibitors retain an ATP-driven sodium transport system. The evidence includes the findings that (i) accumulation of 22Na+ by these vesicles is resistant to reagents that dissipate the protonmotive force but requires ATP and (ii) the vesicles contain a sodium-stimulated ATPase that is distinct from F1F0 ATPase, and whose presence is correlated with sodium transport activity. Sodium movements appear to be electroneutral and are accompanied by movement of H+ in the opposite direction. When membranes are incubated in the absence of protease inhibitors, a secondary Na+/H+ antiport activity emerges, possibly by degradation of the sodium pump. We suggest that S. faecalis expels Na+ by means of an ATP-driven primary transport system that mediates exchange of Na+ for H+. The Na+/H+ antiporter seen in earlier membrane preparation is an artefact of proteolytic degradation.

Adenosine Triphosphatases↗
PubMed2001

Effects of extracellular calcium and potassium on the sodium pump of rat adrenal glomerulosa cells.

Because the activity of the sodium pump (Na-K-ATPase) influences the secretion of aldosterone, we determined how extracellular potassium (K(o)) and calcium affect sodium pump activity in rat adrenal glomerulosa cells. Sodium pump activity was measured as ouabain-sensitive (86)Rb uptake in freshly dispersed cells containing 20 mM sodium as measured with sodium-binding benzofluran isophthalate. Increasing K(o) from 4 to 10 mM in the presence of 1.8 mM extracellular calcium (Ca(o)) stimulated sodium pump activity up to 165% and increased intracellular free calcium as measured with fura 2. Increasing K(o) from 4 to 10 mM in the absence of Ca(o) stimulated the sodium pump approximately 30% and did not increase intracellular free calcium concentration ([Ca(2+)](i)). In some experiments, addition of 1.8 mM Ca(o) in the presence of 4 mM K(o) increased [Ca(2+)](i) above the levels observed in the absence of Ca(o) and stimulated the sodium pump up to 100%. Ca-dependent stimulation of the sodium pump by K(o) and Ca(o) was inhibited by isradipine (10 microM), a blocker of L- and T-type calcium channels, by compound 48/80 (40 microg/ml) and calmidizolium (10 microM), which inhibits calmodulin (CaM), and by KN-62 (10 microM), which blocks some forms of Ca/CaM kinase II (CaMKII). Staurosporine (1 microM), which effectively blocks most forms of protein kinase C, had no effect. In the presence of A-23187, a calcium ionophore, the addition of 0.1 mM Ca(o) increased [Ca(2+)](i) to the level observed in the presence of 10 mM K(o) and 1.8 mM Ca(o) and stimulated the sodium pump 100%. Ca-dependent stimulation by A-23187 and 0.1 mM Ca(o) was not reduced by isradipine but was blocked by KN-62. Thus, under the conditions that K(o) stimulates aldosterone secretion, it stimulates the sodium pump by two mechanisms: direct binding to the pump and by increasing calcium influx, which is dependent on Ca(o). The resulting increase in [Ca(2+)](i) may stimulate the sodium pump by activating CaM and/or CaMKII.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗