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Gene Review

Slc9a1  -  solute carrier family 9 (sodium/hydrogen...

Mus musculus

Synonyms: AW554487, Apnh, NHE-1, Na(+)/H(+) exchanger 1, Nhe1, ...
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Disease relevance of Slc9a1

  • METHODS AND RESULTS: Fluorometric measurements in isolated adult cardiomyocytes demonstrated that cardiac hypertrophy in GC-A(-/-) mice was associated with enhanced NHE-1 activity, alkalinization of intracellular pH, and increased Ca2+ levels [1].
  • Chronic treatment of GC-A(-/-) mice with the NHE-1 inhibitor cariporide normalized cardiomyocyte pH and Ca2+ levels and regressed cardiac hypertrophy and fibrosis, despite persistent arterial hypertension [1].
  • Together, our data suggest that ERK1/2 is involved in activation of NHE1 in astrocytes after in vitro ischemia [2].
  • We hypothesize that the increased neuronal excitability and possibly the seizure disorder in mice lacking the NHE1 is due, at least in part, to changes in Na(+) channel expression and/or regulation [3].
  • These data directly demonstrate that acinar cell hypertrophy induced by chronic beta(1)-adrenergic receptor stimulation occurs independently of NHE1 activity [4].

High impact information on Slc9a1

  • The "housekeeping" sodium/hydrogen exchanger, NHE1, mediates the electroneutral 1:1 exchange of Na+ and H+ across the plasma membrane [5].
  • NHE1 is ubiquitous and is studied extensively for regulation of pHi, cell volume, and response to growth factors [5].
  • The probe detects gene amplification in Na+/H+ antiporter "overexpressers" and a single class of mRNA of ca. 5.6 kb in human, mouse, and hamster cells [6].
  • The data indicate that IFN-gamma initiates rapid exchange of Na+ and H+ by means of the Na+/H+ antiporter and that these amiloride-sensitive ion fluxes are important to some of the genomic effects of IFN-gamma [7].
  • However, elimination of the NHE1 gene fails to cause infertility, suggesting that normal sperm function is maintained in NHE1-null animals [8].

Chemical compound and disease context of Slc9a1


Biological context of Slc9a1

  • Targeted disruption of the Nhe1 gene prevents muscarinic agonist-induced up-regulation of Na(+)/H(+) exchange in mouse parotid acinar cells [12].
  • Salivation in response to pilocarpine stimulation was reduced significantly in both Nhe1(-/-) and Nhe2(-/-) mice, particularly during prolonged stimulation, whereas the loss of NHE3 had no effect on secretion [13].
  • Fluctuations in pHi could potentially have major effects on Ca2+ signaling following secretagogue stimulation; however, the targeted disruption of Nhe1 was found to have no significant effect on intracellular Ca2+ homeostasis [14].
  • The slow-wave epilepsy mouse phenotype is the result of loss of function of the ubiquitous sodium hydrogen exchanger NHEI [15].
  • Migration in a wounding assay was impaired in fibroblasts expressing NHE1 with mutations that independently disrupt ERM binding and cytoskeletal anchoring or ion transport [16].

Anatomical context of Slc9a1

  • Immunohistochemistry indicated that NHE1 was localized to the basolateral and NHE2 to apical membranes of both acinar and duct cells, whereas NHE3 was restricted to the apical region of duct cells [13].
  • Mice with targeted disruptions of the Nhe1, Nhe2, and Nhe3 genes were used to study the in vivo functions of these exchangers in parotid glands [13].
  • Although multiple NHE isoforms (NHE1, NHE2, and NHE3) have been identified in salivary glands, little is known about their specific function(s) in resting and secreting acinar cells [12].
  • In murine macrophages, which were found by RT-PCR to express the NHE-1 isoform of the antiporter, reverse (intracellular Na(+)-driven) Na+/H+ exchange caused a cytosolic acidification and activated an outward current, whereas forward (extracellular Na(+)-driven) exchange produced a cytosolic alkalinization and reduced a basal outward current [17].
  • These results demonstrate that NHE1 is critical for regulating pHi during a muscarinic agonist-stimulated acid challenge and probably plays an important role in regulating fluid secretion in the sublingual exocrine gland [18].

Associations of Slc9a1 with chemical compounds

  • Basolateral Na(+)-dependent H(+) efflux in the microperfused duct was inhibited by 1.5 microM of the amiloride analogue HOE 694, consistent with expression of NHE1, whereas the luminal activity required 50 microM HOE 694 for effective inhibition, suggesting that the efflux might be mediated by NHE2 [19].
  • Mice homozygous for Nhe-1 developed diabetes after cyclophosphamide treatment, but heterozygotes were largely protected from disease [20].
  • Transepithelial HCO3- absorption is defective in renal thick ascending limbs from Na+/H+ exchanger NHE1 null mutant mice [21].
  • Inhibition of HCO(3)(-) absorption by vasopressin and stimulation by hyposmolality, both of which regulate MTAL HCO(3)(-) absorption through primary effects on apical Na(+)/H(+) exchange, were similar in wild-type and NHE1(-/-) MTALs [21].
  • Bradykinin-mediated intracellular Ca2+ transient in NHE1+/+ astrocytes was increased by approximately 84% after OGD/REOX [2].
  • Dimethylamiloride, a classic blocker of Na(+)/H(+) exchange, did not affect pH(c) but increased insulin secretion in NHE1 mutant islets, indicating unspecific effects [22].

Enzymatic interactions of Slc9a1

  • Recombinant caspase-3 cleaved the in vitro-translated NHE1 cytoplasmic domain into five distinct peptides, identical in molecular weight to NHE1 degradation products derived from staurosporine-stimulated RTC lysates [23].

Regulatory relationships of Slc9a1


Other interactions of Slc9a1


Analytical, diagnostic and therapeutic context of Slc9a1


  1. Enhanced activity of the myocardial Na+/H+ exchanger NHE-1 contributes to cardiac remodeling in atrial natriuretic peptide receptor-deficient mice. Kilic, A., Velic, A., De Windt, L.J., Fabritz, L., Voss, M., Mitko, D., Zwiener, M., Baba, H.A., van Eickels, M., Schlatter, E., Kuhn, M. Circulation (2005) [Pubmed]
  2. Stimulation of astrocyte Na+/H+ exchange activity in response to in vitro ischemia depends in part on activation of ERK1/2. Kintner, D.B., Look, A., Shull, G.E., Sun, D. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  3. Increased neuronal excitability and seizures in the Na(+)/H(+) exchanger null mutant mouse. Gu, X.Q., Yao, H., Haddad, G.G. Am. J. Physiol., Cell Physiol. (2001) [Pubmed]
  4. Targeted disruption of the Nhe1 gene fails to inhibit beta(1)-adrenergic receptor-induced parotid gland hypertrophy. Melvin, J.E., Nguyen, H.V., Nehrke, K., Schreiner, C.M., Ten Hagen, K.G., Scott, W. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  5. Sodium/hydrogen exchanger gene defect in slow-wave epilepsy mutant mice. Cox, G.A., Lutz, C.M., Yang, C.L., Biemesderfer, D., Bronson, R.T., Fu, A., Aronson, P.S., Noebels, J.L., Frankel, W.N. Cell (1997) [Pubmed]
  6. Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+/H+ antiporter. Sardet, C., Franchi, A., Pouysségur, J. Cell (1989) [Pubmed]
  7. Role of Na+/H+ exchange by interferon-gamma in enhanced expression of JE and I-A beta genes. Prpic, V., Yu, S.F., Figueiredo, F., Hollenbach, P.W., Gawdi, G., Herman, B., Uhing, R.J., Adams, D.O. Science (1989) [Pubmed]
  8. A new sperm-specific Na+/H+ exchanger required for sperm motility and fertility. Wang, D., King, S.M., Quill, T.A., Doolittle, L.K., Garbers, D.L. Nat. Cell Biol. (2003) [Pubmed]
  9. Role of Na(+)/H(+) exchanger during O(2) deprivation in mouse CA1 neurons. Yao, H., Gu, X.Q., Douglas, R.M., Haddad, G.G. Am. J. Physiol., Cell Physiol. (2001) [Pubmed]
  10. Monoclonal antibody that binds to the central loop of the Tn10-encoded metal tetracycline/H+ antiporter of Escherichia coli. Nada, S., Murakami, S., Okamoto, S., Kubo, Y., Yamaguchi, A. J. Biochem. (2001) [Pubmed]
  11. Anticonvulsant effect of amiloride in pentetrazole-induced status epilepticus in mice. Ali, A., Pillai, K.P., Ahmad, F.J., Dua, Y., Vohora, D. Pharmacological reports : PR. (2006) [Pubmed]
  12. Targeted disruption of the Nhe1 gene prevents muscarinic agonist-induced up-regulation of Na(+)/H(+) exchange in mouse parotid acinar cells. Evans, R.L., Bell, S.M., Schultheis, P.J., Shull, G.E., Melvin, J.E. J. Biol. Chem. (1999) [Pubmed]
  13. Defective fluid secretion and NaCl absorption in the parotid glands of Na+/H+ exchanger-deficient mice. Park, K., Evans, R.L., Watson, G.E., Nehrke, K., Richardson, L., Bell, S.M., Schultheis, P.J., Hand, A.R., Shull, G.E., Melvin, J.E. J. Biol. Chem. (2001) [Pubmed]
  14. Critical role for NHE1 in intracellular pH regulation in pancreatic acinar cells. Brown, D.A., Melvin, J.E., Yule, D.I. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) [Pubmed]
  15. Mouse models of spike-wave epilepsy. Barclay, J., Rees, M. Epilepsia (1999) [Pubmed]
  16. Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. Denker, S.P., Barber, D.L. J. Cell Biol. (2002) [Pubmed]
  17. The mammalian Na+/H+ antiporters NHE-1, NHE-2, and NHE-3 are electroneutral and voltage independent, but can couple to an H+ conductance. Demaurex, N., Orlowski, J., Brisseau, G., Woodside, M., Grinstein, S. J. Gen. Physiol. (1995) [Pubmed]
  18. Muscarinic receptor-induced acidification in sublingual mucous acinar cells: loss of pH recovery in Na+-H+ exchanger-1 deficient mice. Nguyen, H.V., Shull, G.E., Melvin, J.E. J. Physiol. (Lond.) (2000) [Pubmed]
  19. Na(+)-dependent transporters mediate HCO(3)(-) salvage across the luminal membrane of the main pancreatic duct. Lee, M.G., Ahn, W., Choi, J.Y., Luo, X., Seo, J.T., Schultheis, P.J., Shull, G.E., Kim, K.H., Muallem, S. J. Clin. Invest. (2000) [Pubmed]
  20. Genetic and physiological association of diabetes susceptibility with raised Na+/H+ exchange activity. Morahan, G., McClive, P., Huang, D., Little, P., Baxter, A. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  21. Transepithelial HCO3- absorption is defective in renal thick ascending limbs from Na+/H+ exchanger NHE1 null mutant mice. Good, D.W., Watts, B.A., George, T., Meyer, J.W., Shull, G.E. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  22. Glucose-induced cytosolic pH changes in beta-cells and insulin secretion are not causally related: studies in islets lacking the Na+/H+ exchangeR NHE1. Stiernet, P., Nenquin, M., Moulin, P., Jonas, J.C., Henquin, J.C. J. Biol. Chem. (2007) [Pubmed]
  23. Renal tubular epithelial cell apoptosis is associated with caspase cleavage of the NHE1 Na+/H+ exchanger. Wu, K.L., Khan, S., Lakhe-Reddy, S., Wang, L., Jarad, G., Miller, R.T., Konieczkowski, M., Brown, A.M., Sedor, J.R., Schelling, J.R. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  24. Cell shrinkage regulates Src kinases and induces tyrosine phosphorylation of cortactin, independent of the osmotic regulation of Na+/H+ exchangers. Kapus, A., Szászi, K., Sun, J., Rizoli, S., Rotstein, O.D. J. Biol. Chem. (1999) [Pubmed]
  25. Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures. Bell, S.M., Schreiner, C.M., Schultheis, P.J., Miller, M.L., Evans, R.L., Vorhees, C.V., Shull, G.E., Scott, W.J. Am. J. Physiol. (1999) [Pubmed]
  26. Role of protein kinase C and transcription factor AP-1 in the acid-induced increase in Na/H antiporter activity. Horie, S., Moe, O., Yamaji, Y., Cano, A., Miller, R.T., Alpern, R.J. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  27. Inhibition of the Na(+)/H(+) antiporter suppresses IL-12 p40 production by mouse macrophages. Németh, Z.H., Mabley, J.G., Deitch, E.A., Szabó, C., Haskó, G. Biochim. Biophys. Acta (2001) [Pubmed]
  28. Enhanced formation of a HCO3- transport metabolon in exocrine cells of Nhe1-/- mice. Gonzalez-Begne, M., Nakamoto, T., Nguyen, H.V., Stewart, A.K., Alper, S.L., Melvin, J.E. J. Biol. Chem. (2007) [Pubmed]
  29. Localization of Idd11 using NOD congenic mouse strains: elimination of Slc9a1 as a candidate gene. Brodnicki, T.C., McClive, P., Couper, S., Morahan, G. Immunogenetics (2000) [Pubmed]
  30. NHERF and regulation of the renal sodium-hydrogen exchanger NHE3. Weinman, E.J., Cunningham, R., Shenolikar, S. Pflugers Arch. (2005) [Pubmed]
  31. Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Shenolikar, S., Voltz, J.W., Minkoff, C.M., Wade, J.B., Weinman, E.J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  32. Intracellular pH regulation of CA1 neurons in Na(+)/H(+) isoform 1 mutant mice. Yao, H., Ma, E., Gu, X.Q., Haddad, G.G. J. Clin. Invest. (1999) [Pubmed]
  33. alpha(1)-Adrenergic receptors activate NHE1 and NHE3 through distinct signaling pathways in epithelial cells. Liu, F., Gesek, F.A. Am. J. Physiol. Renal Physiol. (2001) [Pubmed]
  34. Membrane-limited expression and regulation of Na+-H+ exchanger isoforms by P2 receptors in the rat submandibular gland duct. Lee, M.G., Schultheis, P.J., Yan, M., Shull, G.E., Bookstein, C., Chang, E., Tse, M., Donowitz, M., Park, K., Muallem, S. J. Physiol. (Lond.) (1998) [Pubmed]
  35. The Na+/H+ antiporter: a "melt" polymorphism allows regional mapping to the short arm of chromosome 1. Dudley, C.R., Giuffra, L.A., Tippett, P., Kidd, K.K., Reeders, S.T. Hum. Genet. (1990) [Pubmed]
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