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Gene Review

NHX1  -  bifunctional K:H/Na:H antiporter NHX1

Saccharomyces cerevisiae S288c

Synonyms: D9461.40, Endosomal/prevacuolar Na(+)/H(+) exchanger, Endosomal/prevacuolar sodium/hydrogen exchanger, NHA2, VPL27, ...
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Disease relevance of NHX1


High impact information on NHX1

  • Herein we describe the use of novel, compartment-specific pH indicators to demonstrate that yeast Nhx1, an endosomal member of the ubiquitous NHE family of Na+/H+ exchangers, regulates luminal and cytoplasmic pH to control vesicle trafficking out of the endosome [2].
  • We conclude that Gyp6 is a negative regulator of Nhx1-dependent trafficking out of the PVC [3].
  • LeNHX2 complements the salt- and hygromycin-sensitive phenotype caused by NHX1 gene disruption in yeast, but affects accumulation of K+ and not Na+ in intracellular compartments [4].
  • The LeNHX2 protein, belonging to a subfamily of plant NHX proteins closely related to the yeast NHX1 protein, is abundant in roots and stems and is induced in leaves by short term salt or abscisic acid treatment [4].
  • Our analysis of the glycosylation of Nhx1 is strongly indicative of residence of at least some portion of the hydrophilic tail domain within the endosomal lumen [5].

Biological context of NHX1

  • We show that NHX1, a novel gene homologous to the mammalian NHE family of Na+/H+ exchangers, is required for Na+ sequestration in yeast and contributes to the Na+-tolerant phenotype of pma1-alpha4 [6].
  • The deduced amino acid sequence is similar to that of NHX1 and NHE isoforms in mammals, and shares high similarity with the sequences within predicted transmembrane segments and an amiloride-binding domain [7].
  • Based on these findings, Kha1p is probably not localized in plasma membrane and does not mediate efflux of alkali metal cations from cells, but is important for the regulation of intracellular cation homeostasis and optimal pH control, similarly as the Nhx1p [8].
  • The Saccharomyces cerevisiae genome contains three genes encoding alkali metal cation/H+ antiporters (Nha1p, Nhx1p, Kha1p) that differ in cell localization, substrate specificity and physiological function [9].
  • The high sequence conservation within this subfamily of yeast antiporters suggests that Nhx1p is of great importance in cell physiology [9].

Anatomical context of NHX1

  • Since the NHX1 genes that promote the transport of Na+ into the vacuoles have been regarded to be involved in salt tolerance by accumulating Na+ in the vacuoles, we can add a new biological role for blue flower coloration in the Japanese morning glory by the vacuolar alkalization [10].
  • In this context, we show that the yeast NHE homologue, Nhx1 (Nass, R., Cunningham, K. W., and Rao, R. (1997) J. Biol. Chem. 272, 26145-26152), localizes uniquely to prevacuolar compartments, equivalent to late endosomes of animal cells [11].
  • To assess the function of Nha2, we deleted the NHA2 gene by homologous disruption and found that benzamil-inhibitable, acid-activated 22Na+ uptake into mitochondria was abolished in the mutant strain [12].
  • Our results show that efficient transport out of the prevacuolar compartment requires Nhx1p, and that nhx1 delta cells exhibit phenotypes characteristic of the "class E" group of vps mutants [13].

Associations of NHX1 with chemical compounds


Other interactions of NHX1

  • Disruption of NHX1 or NHA1, encoding known Na(+)/H(+) antiporters, did not result in the loss of (22)Na(+) uptake or the alkaline cation-dependent DeltapH decrease [14].

Analytical, diagnostic and therapeutic context of NHX1

  • The trafficking phenotypes of all Nhx1 mutants, including hygromycin-sensitivity and missorting of carboxypeptidase Y, were found to directly correlate with pH homoeostasis defects and could be proportionately corrected by titration with weak base [15].


  1. Loss of the homotypic fusion and vacuole protein sorting or golgi-associated retrograde protein vesicle tethering complexes results in gentamicin sensitivity in the yeast Saccharomyces cerevisiae. Wagner, M.C., Molnar, E.E., Molitoris, B.A., Goebl, M.G. Antimicrob. Agents Chemother. (2006) [Pubmed]
  2. The yeast endosomal Na+K+/H+ exchanger Nhx1 regulates cellular pH to control vesicle trafficking. Brett, C.L., Tukaye, D.N., Mukherjee, S., Rao, R. Mol. Biol. Cell (2005) [Pubmed]
  3. Inhibition of sodium/proton exchange by a Rab-GTPase-activating protein regulates endosomal traffic in yeast. Ali, R., Brett, C.L., Mukherjee, S., Rao, R. J. Biol. Chem. (2004) [Pubmed]
  4. A novel intracellular K+/H+ antiporter related to Na+/H+ antiporters is important for K+ ion homeostasis in plants. Venema, K., Belver, A., Marin-Manzano, M.C., Rodríguez-Rosales, M.P., Donaire, J.P. J. Biol. Chem. (2003) [Pubmed]
  5. The yeast Na+/H+ exchanger Nhx1 is an N-linked glycoprotein. Topological implications. Wells, K.M., Rao, R. J. Biol. Chem. (2001) [Pubmed]
  6. Intracellular sequestration of sodium by a novel Na+/H+ exchanger in yeast is enhanced by mutations in the plasma membrane H+-ATPase. Insights into mechanisms of sodium tolerance. Nass, R., Cunningham, K.W., Rao, R. J. Biol. Chem. (1997) [Pubmed]
  7. Molecular cloning and expression of the Na+/H+ exchanger gene in Oryza sativa. Fukuda, A., Nakamura, A., Tanaka, Y. Biochim. Biophys. Acta (1999) [Pubmed]
  8. Physiological characterization of Saccharomyces cerevisiae kha1 deletion mutants. Maresova, L., Sychrova, H. Mol. Microbiol. (2005) [Pubmed]
  9. Exploration of yeast alkali metal cation/H+ antiporters: sequence and structure comparison. Pribylov??, L., Papouskov??, K., Zavrel, M., Souciet, J.L., Sychrov??, H. Folia Microbiol. (Praha) (2006) [Pubmed]
  10. Genes encoding the vacuolar Na+/H+ exchanger and flower coloration. Yamaguchi, T., Fukada-Tanaka, S., Inagaki, Y., Saito, N., Yonekura-Sakakibara, K., Tanaka, Y., Kusumi, T., Iida, S. Plant Cell Physiol. (2001) [Pubmed]
  11. Novel localization of a Na+/H+ exchanger in a late endosomal compartment of yeast. Implications for vacuole biogenesis. Nass, R., Rao, R. J. Biol. Chem. (1998) [Pubmed]
  12. Identification of a mitochondrial Na+/H+ exchanger. Numata, M., Petrecca, K., Lake, N., Orlowski, J. J. Biol. Chem. (1998) [Pubmed]
  13. The sodium/proton exchanger Nhx1p is required for endosomal protein trafficking in the yeast Saccharomyces cerevisiae. Bowers, K., Levi, B.P., Patel, F.I., Stevens, T.H. Mol. Biol. Cell (2000) [Pubmed]
  14. Sodium and sulfate ion transport in yeast vacuoles. Hirata, T., Wada, Y., Futai, M. J. Biochem. (2002) [Pubmed]
  15. Mutational analysis of the intramembranous H10 loop of yeast Nhx1 reveals a critical role in ion homoeostasis and vesicle trafficking. Mukherjee, S., Kallay, L., Brett, C.L., Rao, R. Biochem. J. (2006) [Pubmed]
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