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Gene Review

Slc9a2  -  solute carrier family 9 (sodium/hydrogen...

Mus musculus

Synonyms: 2210416H12Rik, 4932415O19Rik, AV333884, NHE2
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Disease relevance of Slc9a2


High impact information on Slc9a2

  • As the distribution of NHE3 overlaps with that of the NHE2 isoform in kidney and intestine, the function and relative importance of NHE3 in vivo is unclear [3].
  • 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 [4].
  • To study the roles of Na(+)-dependent H(+) transporters, we characterized H(+) efflux mechanisms in the pancreatic duct in wild-type, NHE2(-/-), and NHE3(-/-) mice [4].
  • This suggests that the unique sensitivity of NHE2 to inhibition by extracellular H+, which would allow upregulation of its activity by the increased interstitial alkalinity that accompanies acid secretion, might enable this isoform to play a specialized role in maintaining the long-term viability of the parietal cell [5].
  • The sodium content, chloride activity and osmolality of saliva in Nhe2(-/-) or Nhe3(-/-) mice were comparable with those of wild-type mice [6].

Biological context of Slc9a2

  • These results negate the hypothesis that NHE2 plays an important renal function in sodium-fluid volume homeostasis; however, they demonstrate that NHE3 is critical for systemic electrolyte, acid-base, and fluid volume homeostasis during dietary Na+ restriction and that its absence leads to renal salt wasting [7].
  • After 15 days of Na+ restriction, blood pressure, fractional excretion of Na+, and the glomerular filtration rate (GFR) of Nhe2-/-Nhe3+/- mice were similar to those of Nhe2+/+ and Nhe3+/- mice, and no metabolic disturbances were observed [7].
  • The aim of this study was to define its expression, location, and regulatory properties in murine colon and to look for the compensatory changes in NHE2 (-/-) colon that allow normal histology and absorptive function [8].
  • We conclude that in rabbit gastric epithelium, NHE1 and NHE4 regulate cell volume and NHE1 and NHE2 regulate pH(i) [9].
  • Subcloning and sequencing of the PCR product from mouse MTAL revealed 91% and 75% identity to the published NHE2 nucleotide sequence of comparable regions in rat and rabbit, respectively [10].

Anatomical context of Slc9a2

  • 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 [6].
  • 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 [11].
  • On the basis of the effects of low [Na(+)](o) and inhibitors we propose that acid extrusion in duodenal epithelial cells involves Na(+)/H(+) exchange by isoforms NHE1, NHE2, and NHE3 [12].
  • Northern blots of poly(A) mRNA extracts of the cell lines revealed a low abundance of transcripts for NHE-2, -3 and -4, with no systematic difference between the lines [13].
  • This study represents the first description of the functional co-operation of PEPT2 and NHE1 and/or NHE2 in cerebrocortical astrocytes [14].

Associations of Slc9a2 with chemical compounds

  • The lack of NHE1, but not NHE2 or NHE3, prevented intracellular pH recovery from an acid load in resting acinar cells, in acini stimulated to secrete with the muscarinic agonist carbachol, and in acini shrunken by hypertonic addition of sucrose [11].
  • The results indicate that the basolaterally located NHE1, NHE2, and NHE4, in addition to participating in the homeostatic control of intracellular pH, may play a role in H(+) extrusion in order to achieve transepithelial HCO(3)(-) secretion [15].
  • A general NHE inhibitor, 5-(N-ethyl-N-isopropyl)amiloride (EIPA; 20 muM), inhibited pH(i) recovery in NHE2-null mice (46%) but less strongly than in wild-type mice (74%), suggesting both EIPA-sensitive and -insensitive compensatory mechanisms [16].
  • Our results demonstrate high NHE2 expression in the crypts and suggest a role for NHE2 in cryptal pH(i) and volume homeostasis [8].
  • In vivo microperfusion of rat distal tubules suggests that a significant fraction of bicarbonate reabsorption in this nephron segment is mediated by NHE2 [17].

Regulatory relationships of Slc9a2

  • Salivarectomy did not influence NHE-2 protein expression and inhibited the increased NHE-3 protein expression following SBR [18].

Other interactions of Slc9a2

  • These results suggest that in parotid duct cells apical NHE2 and NHE3 do not play a major role in Na(+) absorption [6].
  • Immunostaining showed that NHE1, NHE2, and NHE4 were present in both apical and basolateral membranes [15].
  • We further analyzed the transcriptional regulation of NHE-2 by members of the Sp1 multigene family [19].

Analytical, diagnostic and therapeutic context of Slc9a2

  • NHE1, NHE2, and NHE3 were expressed at the mRNA level (RT-PCR) as well as at the protein level (Western blot analysis) [12].
  • The Na/H antiporters NHE-1, NHE-2, and NHE-3 mRNAs were detected by reverse transcription-polymerase chain reaction (RT-PCR) [20].
  • Analysis of PCR products with and without digestion by restriction enzymes chosen from the published NHE2 sequence gave predicted sizes [10].


  1. Impaired gastric acid secretion in mice with a targeted disruption of the NHE4 Na+/H+ exchanger. Gawenis, L.R., Greeb, J.M., Prasad, V., Grisham, C., Sanford, L.P., Doetschman, T., Andringa, A., Miller, M.L., Shull, G.E. J. Biol. Chem. (2005) [Pubmed]
  2. Variant form of diffuse corporal gastritis in NHE2 knockout mice. Boivin, G.P., Schultheis, P.J., Shull, G.E., Stemmermann, G.N. Comp. Med. (2000) [Pubmed]
  3. Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger. Schultheis, P.J., Clarke, L.L., Meneton, P., Miller, M.L., Soleimani, M., Gawenis, L.R., Riddle, T.M., Duffy, J.J., Doetschman, T., Wang, T., Giebisch, G., Aronson, P.S., Lorenz, J.N., Shull, G.E. Nat. Genet. (1998) [Pubmed]
  4. 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]
  5. Targeted disruption of the murine Na+/H+ exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion. Schultheis, P.J., Clarke, L.L., Meneton, P., Harline, M., Boivin, G.P., Stemmermann, G., Duffy, J.J., Doetschman, T., Miller, M.L., Shull, G.E. J. Clin. Invest. (1998) [Pubmed]
  6. 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]
  7. Renal salt wasting in mice lacking NHE3 Na+/H+ exchanger but not in mice lacking NHE2. Ledoussal, C., Lorenz, J.N., Nieman, M.L., Soleimani, M., Schultheis, P.J., Shull, G.E. Am. J. Physiol. Renal Physiol. (2001) [Pubmed]
  8. The Na+/H+ exchanger isoform 2 is the predominant NHE isoform in murine colonic crypts and its lack causes NHE3 upregulation. Bachmann, O., Riederer, B., Rossmann, H., Groos, S., Schultheis, P.J., Shull, G.E., Gregor, M., Manns, M.P., Seidler, U. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  9. Differential expression and regulation of Na(+)/H(+) exchanger isoforms in rabbit parietal and mucous cells. Rossmann, H., Sonnentag, T., Heinzmann, A., Seidler, B., Bachmann, O., Vieillard-Baron, D., Gregor, M., Seidler, U. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  10. Na+/H+ exchanger isoform 2 (NHE2) is expressed in the apical membrane of the medullary thick ascending limb. Sun, A.M., Liu, Y., Dworkin, L.D., Tse, C.M., Donowitz, M., Yip, K.P. J. Membr. Biol. (1997) [Pubmed]
  11. 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]
  12. NHE1, NHE2, and NHE3 contribute to regulation of intracellular pH in murine duodenal epithelial cells. Praetorius, J., Andreasen, D., Jensen, B.L., Ainsworth, M.A., Friis, U.G., Johansen, T. Am. J. Physiol. Gastrointest. Liver Physiol. (2000) [Pubmed]
  13. Na+/H+ exchanger activity and phosphorylation in temperature-sensitive immortalized proximal tubule cell lines derived from the spontaneously hypertensive rat. Ng, L.L., Jennings, S., Davies, J.E., Quinn, P.A. Clin. Sci. (2000) [Pubmed]
  14. Functional linkage of H+/peptide transporter PEPT2 and Na+/H+ exchanger in primary cultures of astrocytes from mouse cerebral cortex. Wada, M., Miyakawa, S., Shimada, A., Okada, N., Yamamoto, A., Fujita, T. Brain Res. (2005) [Pubmed]
  15. Expression, immunolocalization, and functional activity of Na+/H+ exchanger isoforms in mouse endometrial epithelium. Wang, X.F., Yu, M.K., Lam, S.Y., Leung, K.M., Jiang, J.L., Leung, P.S., Ko, W.H., Leung, P.Y., Chew, S.B., Liu, C.Q., Tse, C.M., Chan, H.C. Biol. Reprod. (2003) [Pubmed]
  16. NHE2 is the main apical NHE in mouse colonic crypts but an alternative Na+-dependent acid extrusion mechanism is upregulated in NHE2-null mice. Guan, Y., Dong, J., Tackett, L., Meyer, J.W., Shull, G.E., Montrose, M.H. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  17. NHE2-mediated bicarbonate reabsorption in the distal tubule of NHE3 null mice. Bailey, M.A., Giebisch, G., Abbiati, T., Aronson, P.S., Gawenis, L.R., Shull, G.E., Wang, T. J. Physiol. (Lond.) (2004) [Pubmed]
  18. Differential expression of ileal Na(+)/H(+) exchanger isoforms after enterectomy. Falcone, R.A., Shin, C.E., Stern, L.E., Wang, Z., Erwin, C.R., Soleimani, M., Warner, B.W. J. Surg. Res. (1999) [Pubmed]
  19. Transcriptional regulation of rat Na(+)/H(+) exchanger isoform-2 (NHE-2) gene by Sp1 transcription factor. Bai, L., Collins, J.F., Xu, H., Ghishan, F.K. Am. J. Physiol., Cell Physiol. (2001) [Pubmed]
  20. Kidney cortex cells derived from SV40 transgenic mice retain intrinsic properties of polarized proximal tubule cells. Chalumeau, C., Lamblin, D., Bourgeois, S., Borensztein, P., Chambrey, R., Bruneval, P., Huyen, J.P., Froissart, M., Biber, J., Paillard, M., Kellermann, O., Poggioli, J. Kidney Int. (1999) [Pubmed]
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