The Na+/H+ exchanger: an update on structure, regulation and cardiac physiology

Fliegel, Larry; Fröhlich, Otto

doi:10.1042/bj2960273

Cited by 115 publications

(42 citation statements)

References 126 publications

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“…DISCUSSION Na+/H+ antiporters exchange Na+ and H+ ions, with the direction of exchange being determined by the gradients of the two ions across the cell membrane. In mammalian cells, the predominant function of the Na+/H+ exchanger is to regulate intracellular pH by transporting protons out of the cell in exchange for sodium (21). In contrast, the S. pombe Na+/H+ antiporter encoded by sod2 functions to regulate the internal concentration of sodium, rather than protons, and previous studies have measured the influx of protons as sodium is exported from cells expressing this antiporter (3).…”

Section: Resultsmentioning

confidence: 99%

Functional expression of the Schizosaccharomyces pombe Na+/H+ antiporter gene, sod2, in Saccharomyces cerevisiae.

Hahnenberger¹,

Jia²,

Young³

1996

Proc. Natl. Acad. Sci. U.S.A.

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In the fission yeast, Schizosaccharomyces pombe, tolerance to high sodium and lithium concentrations requires the functioning of the sod2, Na+/H+ antiporter. We have directly measured the activity of this antiporter and demonstrated reconstitution of the activity in gene deletion strains. In addition, we have shown that it can be transferred to, and its antiporter activity detected in, the budding yeast, Saccharomyces cerevisiae, where it also confers sodium and lithium tolerance. Proton flux through the S. pombe Na+/H+ antiporter was directly measured using microphysiometry. The direction of transmembrane proton flux mediated by this antiporter was reversible, with protons being imported or exported in response to the external concentration of sodium. This bidirectional activity was also detected in S. cerevisiae strains expressing sod2 and expression of this gene complemented the sodium and lithium sensitivity resulting from inactivation of the ENAI/PMR2 encoded Na+-exporting ATPases. This suggests that antiporters or sodium pumps can be utilized interchangeably by S. cerevisiae to regulate internal sodium concentration. Potent inhibitors of mammalian Na+/ H+ exchangers were found to have no effect on sod2 activity. The proton flux mediated by sod2 was also found to be unaffected by perturbation of membrane potential or the plasma membrane proton gradient.Maintaining low intracellular sodium concentrations is a problem common to almost all cell types because high internal sodium is generally toxic. In animal cells, the Na+,K+-ATPase directly exports sodium and establishes an inwardly directed sodium gradient to drive secondary transport systems. This enzyme is not present in plants and fungi and instead a primary proton gradient is established by the H+-ATPase. Secondary transport systems use the energy in the proton gradient to carry nutrients into the cell. Sodium is removed by specialized export systems (1, 2).Recently the export mechanism for intracellular sodium in fission and budding yeasts has been described and rather surprisingly two quite distinct mechanisms have evolved. In Schizosaccharomyces pombe tolerance to external sodium is dependent upon the sod2 gene, which encodes a protein with homology to bacterial and mammalian Na+/H+ antiporters (3). Na+ or Li' export from these cells is via this carrier and dependent upon the proton gradient established by the H+-ATPase. Deletion of the gene results in Na+ and Li' hypersensitivity. In Saccharomyces cerevisiae, a family of genes encoding Na+-ATPases is responsible for sodium efflux (1, 4). Disruption of these P-type sodium pumps in S. cerevisiae results in a phenotype very similar to disruption of sod2 in S. pombe; the cells become hypersensitive to Na+ and Li+ and cannot export these ions from the cell. Overexpression of the gene causes an increase in Na+ and Li+ tolerance. To date, no antiporter activity has been detected in budding yeast and no Na+-ATPase in fission yeast.We have performed an analysis of Na+/H+ antiporter activity in S. pomb...

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Section: Resultsmentioning

confidence: 99%

Functional expression of the Schizosaccharomyces pombe Na+/H+ antiporter gene, sod2, in Saccharomyces cerevisiae.

Hahnenberger¹,

Jia²,

Young³

1996

Proc. Natl. Acad. Sci. U.S.A.

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“…The relatively higher doses of amiloride which are required to achieve a response in the rat efferent ducts suggests that the efferent duct Na¤-H¤ exchanger is more closely related to isoforms in other transporting epithelia than to the amiloride-sensitive NHE-1 housekeeping form, which is involved in cell pH and volume regulation in most cell types (Fliegel & Fr ohlich, 1993). However, it is not possible from the results of this study to determine whether the functional isoform in the efferent ducts is one of those isoforms (NHE-2, -3 or -4), and further work will be required to resolve this issue.…”

Section: ------------------------------------------------------------mentioning

confidence: 99%

The Role of Na⁺−H⁺ Exchange in Fluid and Solute Transport in the Rat Efferent Ducts

Hansen

Clulow

Jones

1999

Experimental Physiology

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summaryIn vivo microperfusion techniques were used to investigate the role of Na¤-H¤ exchange in the efferent ducts of the rat. Individual efferent ducts were perfused with a Krebs-Ringer bicarbonate solution (KRB) containing 0, 1, 3, 5 or 7·5 mÒ amiloride. Concentrations of 1-5 mÒ amiloride inhibited fluid reabsorption from the efferent ducts in a linear dose-dependent manner with an apparent Km of 3 mÒ. Inhibition was maximal at 5 mÒ with reabsorption reduced by about 70%. The effects of amiloride were completely reversible and there was little effect of amiloride on luminal osmolality and concentrations of Na¤, Cl¦ or K¤.

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“…Our conclusion is clearly consistent with the beneficial effect of Na ϩ /H ϩ exchange inhibitors, which reduces this substrate, whereas it is inconsistent with the hypothesis that Na ϩ entry via Na ϩ /H ϩ exchange just after reperfusion is a critical trigger for reperfusion injury. 31 …”

Section: Determinants Of Functional Recoverymentioning

confidence: 99%

Intracellular Sodium Accumulation During Ischemia as the Substrate for Reperfusion Injury

Imahashi

Kusuoka

Hashimoto

et al. 1999

Circulation Research

158

101

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The Na+/H+ exchanger: an update on structure, regulation and cardiac physiology

Cited by 115 publications

References 126 publications

Functional expression of the Schizosaccharomyces pombe Na+/H+ antiporter gene, sod2, in Saccharomyces cerevisiae.

Functional expression of the Schizosaccharomyces pombe Na+/H+ antiporter gene, sod2, in Saccharomyces cerevisiae.

The Role of Na⁺−H⁺ Exchange in Fluid and Solute Transport in the Rat Efferent Ducts

Intracellular Sodium Accumulation During Ischemia as the Substrate for Reperfusion Injury

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The Na+/H+ exchanger: an update on structure, regulation and cardiac physiology

Cited by 115 publications

References 126 publications

Functional expression of the Schizosaccharomyces pombe Na+/H+ antiporter gene, sod2, in Saccharomyces cerevisiae.

Functional expression of the Schizosaccharomyces pombe Na+/H+ antiporter gene, sod2, in Saccharomyces cerevisiae.

The Role of Na+−H+ Exchange in Fluid and Solute Transport in the Rat Efferent Ducts

Intracellular Sodium Accumulation During Ischemia as the Substrate for Reperfusion Injury

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The Role of Na⁺−H⁺ Exchange in Fluid and Solute Transport in the Rat Efferent Ducts