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Gene Review

Slc9a3  -  solute carrier family 9 (sodium/hydrogen...

Mus musculus

Synonyms: 9030624O13Rik, AI930210, NHE-3, NHE3
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Disease relevance of Slc9a3


High impact information on Slc9a3

  • NHE3 is one of five plasma membrane Na+/H+ exchangers and is encoded by the mouse gene Slc9a3 [5].
  • 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 [5].
  • Plasma aldosterone is increased in NHE3-deficient mice, and expression of both renin and the AE1 (Slc4a1) Cl-/HCO3- exchanger mRNAs are induced in kidney [5].
  • These data show that NHE3 is the major absorptive Na+/H+ exchanger in kidney and intestine, and that lack of the exchanger impairs acid-base balance and Na+-fluid volume homeostasis [5].
  • Both receptor-mediated and fluid-phase endocytosis are affected, and the internalization of the apical transporters NaPi-2 and NHE3 is slowed [6].

Biological context of Slc9a3

  • Mice with targeted disruptions of the Nhe1, Nhe2, and Nhe3 genes were used to investigate the contribution of these proteins to the stimulation-induced up-regulation of NHE activity in mouse parotid acinar cells [7].
  • 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 [8].
  • 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 [1].
  • This was associated with a significant decrease in cAMP-stimulated phosphorylation of NHE3 immunoprecipitated from solubilized NHERF-1 (-/-) BBMs [9].
  • Thus, luminal expression of NHE3 was reduced by 53% in ducts of homozygote DeltaF508 mice [10].

Anatomical context of Slc9a3

  • 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 [11].
  • 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 [8].
  • The epithelial cells in the colon displayed unique adaptive regulation of ion transporters; NHE3 expression was enhanced in the proximal and distal colon, whereas colonic H,K-ATPase and the epithelial sodium channel showed massive up-regulation in the distal colon [12].
  • The expression of NHE2 and NHE3 on intestinal-brush border membranes suggests that both Na(+)/H(+) exchangers serve absorptive functions [13].
  • In the present work, we characterized H(+) and HCO3- transport mechanisms in the submandibular salivary gland (SMG) ducts of wild type, NHE2-/-, NHE3-/-, and NHE2-/-;NHE3-/- double knock-out mice [14].

Associations of Slc9a3 with chemical compounds

  • Notably, the remaining luminal Na(+)-dependent H(+) efflux in ducts from NHE3(-/-) mice was inhibited by 50 microM HOE 694 [11].
  • The sodium content, chloride activity and osmolality of saliva in Nhe2(-/-) or Nhe3(-/-) mice were comparable with those of wild-type mice [8].
  • 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 [7].
  • These in vivo phenotypic correlates of the absorptive defect suggest that the NaCl, HCO, and fluid absorption that is dependent on apical Na(+)/H(+) exchange is due overwhelmingly to the activity of NHE3, with little contribution from NHE2 [13].
  • In the present work, we used molecular, biochemical, and functional approaches to study the regulatory interaction between CFTR and the HCO3- salvage mechanism Na+/H+ exchanger isoform 3 (NHE3) in heterologous expression systems and in the native pancreatic duct [10].

Physical interactions of Slc9a3

  • Opossum kidney (OK) cells were transfected with either empty vector (control), full-length mouse (m) NHERF(1-355), or a truncated mNHERF(1-325) that lacked ezrin binding and had been demonstrated in fibroblasts to bind NHE3 but not mediate its cAMP-associated inhibition [15].
  • In expression systems and in yeast, Na/H exchanger regulatory factor (NHERF)-1 and NHERF-2 have been demonstrated to interact with the renal brush border membrane proteins NHE3 and Npt2 [16].

Regulatory relationships of Slc9a3

  • Forskolin (34.8 +/- 6.2%) and PTH (29.7 +/- 1.8%) inhibited NHE3 activity in wild-type proximal tubule cells but neither forskolin (-3.2 +/- 3.3%) nor PTH (-16.6 +/- 8.1%) inhibited NHE3 activity in NHERF-1(-/-) cells [17].
  • We found that CFTR regulates NHE3 activity by both acute and chronic mechanisms [10].
  • These findings demonstrate a novel role for NHE1 in transepithelial HCO(3)(-) absorption in the MTAL, in which basolateral NHE1 controls the activity of apical NHE3 [18].
  • Salivarectomy did not influence NHE-2 protein expression and inhibited the increased NHE-3 protein expression following SBR [19].
  • Parathyroid hormone (PTH) induced a tenfold increase in cAMP and reduced the Na-dependent phosphate uptake and NHE-3 activity, as observed in proximal tubule cells [20].

Other interactions of Slc9a3

  • However, disruption of NHE2 had no effect on luminal transport, while disruption of the NHE3 gene reduced luminal Na(+)-dependent H(+) efflux by approximately 45% [11].
  • The localization of NaPi-IIa and other proteins interacting with PDZK1 in vitro [Na(+)/H(+) exchanger (NHE3), chloride-formate exchanger (CFEX)/putative anion transporter-1 (PAT1), NHERF1] was not altered in Pdzk1(-/-) mice [21].
  • In the pancreatic duct, CFTR increases expression of NHE3 in the luminal membrane [10].
  • In vivo evidence for interferon-gamma-mediated homeostatic mechanisms in small intestine of the NHE3 Na+/H+ exchanger knockout model of congenital diarrhea [3].
  • We investigated the mechanism of compensation that allows maintenance of sodium balance in NHE3 knockout mice and in NCC knockout mice [22].

Analytical, diagnostic and therapeutic context of Slc9a3


  1. 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]
  2. Endothelin-1/endothelin-B receptor-mediated increases in NHE3 activity in chronic metabolic acidosis. Laghmani, K., Preisig, P.A., Moe, O.W., Yanagisawa, M., Alpern, R.J. J. Clin. Invest. (2001) [Pubmed]
  3. In vivo evidence for interferon-gamma-mediated homeostatic mechanisms in small intestine of the NHE3 Na+/H+ exchanger knockout model of congenital diarrhea. Woo, A.L., Gildea, L.A., Tack, L.M., Miller, M.L., Spicer, Z., Millhorn, D.E., Finkelman, F.D., Hassett, D.J., Shull, G.E. J. Biol. Chem. (2002) [Pubmed]
  4. Renal function in NHE3-deficient mice with transgenic rescue of small intestinal absorptive defect. Woo, A.L., Noonan, W.T., Schultheis, P.J., Neumann, J.C., Manning, P.A., Lorenz, J.N., Shull, G.E. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  5. 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]
  6. ClC-5 Cl- -channel disruption impairs endocytosis in a mouse model for Dent's disease. Piwon, N., Günther, W., Schwake, M., Bösl, M.R., Jentsch, T.J. Nature (2000) [Pubmed]
  7. 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]
  8. 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]
  9. NHERF-1 uniquely transduces the cAMP signals that inhibit sodium-hydrogen exchange in mouse renal apical membranes. Weinman, E.J., Steplock, D., Shenolikar, S. FEBS Lett. (2003) [Pubmed]
  10. Regulatory interaction between the cystic fibrosis transmembrane conductance regulator and HCO3- salvage mechanisms in model systems and the mouse pancreatic duct. Ahn, W., Kim, K.H., Lee, J.A., Kim, J.Y., Choi, J.Y., Moe, O.W., Milgram, S.L., Muallem, S., Lee, M.G. J. Biol. Chem. (2001) [Pubmed]
  11. 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]
  12. slc26a3 (dra)-deficient Mice Display Chloride-losing Diarrhea, Enhanced Colonic Proliferation, and Distinct Up-regulation of Ion Transporters in the Colon. Schweinfest, C.W., Spyropoulos, D.D., Henderson, K.W., Kim, J.H., Chapman, J.M., Barone, S., Worrell, R.T., Wang, Z., Soleimani, M. J. Biol. Chem. (2006) [Pubmed]
  13. Loss of the NHE2 Na(+)/H(+) exchanger has no apparent effect on diarrheal state of NHE3-deficient mice. Ledoussal, C., Woo, A.L., Miller, M.L., Shull, G.E. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  14. HCO3- salvage mechanisms in the submandibular gland acinar and duct cells. Luo, X., Choi, J.Y., Ko, S.B., Pushkin, A., Kurtz, I., Ahn, W., Lee, M.G., Muallem, S. J. Biol. Chem. (2001) [Pubmed]
  15. Ezrin binding domain-deficient NHERF attenuates cAMP-mediated inhibition of Na(+)/H(+) exchange in OK cells. Weinman, E.J., Steplock, D., Wade, J.B., Shenolikar, S. Am. J. Physiol. Renal Physiol. (2001) [Pubmed]
  16. Localization and interaction of NHERF isoforms in the renal proximal tubule of the mouse. Wade, J.B., Liu, J., Coleman, R.A., Cunningham, R., Steplock, D.A., Lee-Kwon, W., Pallone, T.L., Shenolikar, S., Weinman, E.J. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  17. Defective parathyroid hormone regulation of NHE3 activity and phosphate adaptation in cultured NHERF-1-/- renal proximal tubule cells. Cunningham, R., Steplock, D., Wang, F., Huang, H., E, X., Shenolikar, S., Weinman, E.J. J. Biol. Chem. (2004) [Pubmed]
  18. 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]
  19. 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]
  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]
  21. Expression and regulation of the renal Na/phosphate cotransporter NaPi-IIa in a mouse model deficient for the PDZ protein PDZK1. Capuano, P., Bacic, D., Stange, G., Hernando, N., Kaissling, B., Pal, R., Kocher, O., Biber, J., Wagner, C.A., Murer, H. Pflugers Arch. (2005) [Pubmed]
  22. Profiling of renal tubule Na+ transporter abundances in NHE3 and NCC null mice using targeted proteomics. Brooks, H.L., Sorensen, A.M., Terris, J., Schultheis, P.J., Lorenz, J.N., Shull, G.E., Knepper, M.A. J. Physiol. (Lond.) (2001) [Pubmed]
  23. 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]
  24. Angiotensin II stimulates NHE3 activity by exocytic insertion of the transporter: role of PI 3-kinase. du Cheyron, D., Chalumeau, C., Defontaine, N., Klein, C., Kellermann, O., Paillard, M., Poggioli, J. Kidney Int. (2003) [Pubmed]
  25. 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]
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