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Gene Review

Slc12a3  -  solute carrier family 12, member 3

Mus musculus

Synonyms: AI035291, NCC, NCCT, Na-Cl symporter, Ncc, ...
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Disease relevance of Slc12a3


High impact information on Slc12a3

  • This inhibition is independent of WNK4 kinase activity and is mediated by clathrin-dependent endocytosis of ROMK, mechanisms distinct from those that characterize WNK4 inhibition of NCCT [5].
  • Thiazide diuretics enhance renal Na+ excretion by blocking the Na+-Cl- cotransporter (NCC), and mutations in NCC result in Gitelman syndrome [6].
  • Hypomagnesemia developed during chronic HCTZ administration and in NCC-knockout mice, an animal model of Gitelman syndrome, accompanied by downregulation of the epithelial Mg2+ channel transient receptor potential channel subfamily M, member 6 (Trpm6) [6].
  • Mouse WNK4 was cloned and expressed in Xenopus oocytes with or without NCC [7].
  • This effect did not result from defects in NCC synthesis or processing, but was associated with an 85% reduction in NCC abundance at the plasma membrane [7].

Chemical compound and disease context of Slc12a3

  • NCC-deficient mice had significantly elevated plasma aldosterone levels and exhibited hypocalciuria, hypomagnesemia, and compensated alkalosis [8].

Biological context of Slc12a3

  • WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis [9].
  • These data indicate that the loss of NCC activity in the mouse causes only subtle perturbations of sodium and fluid volume homeostasis, but renal handling of Mg2+ and Ca2+ are altered, as observed in Gitelman's syndrome [1].
  • Ion transport kinetics in all mutant clones were similar to wild-type TSC, except in G627V, in which a small but significant increase in affinity for extracellular Cl(-) was observed [10].
  • Profiling of renal tubule Na+ transporter abundances in NHE3 and NCC null mice using targeted proteomics [11].
  • The associated phenotypes due to loss-of-function mutations in NCC and NKCC2 are consistent, in part, with their functional roles in the distal convoluted tubule and thick ascending limb, respectively [12].

Anatomical context of Slc12a3

  • Because WNK4 is a potent inhibitor of members of the cation-cotransporter SLC12A family, we used coexpression studies in Xenopus oocytes to investigate the effect of WNK3 on NCC and NKCC2, related kidney-specific transporters that mediate apical NaCl reabsorption in the thick ascending limb and distal convoluted tubule, respectively [9].
  • Our data show that biochemical and functional properties of the mutant TSCs are similar to wild-type TSC but that the surface expression is reduced, suggesting that these mutations impair the insertion of a functional protein into the plasma membrane [10].
  • We therefore propose that the present in vitro experiments (long-lasting exposure to a high concentration of ET3) mimic the environment encountered by NCC in vivo when they migrate to the skin under the ectoderm that expresses ET3 [13].
  • The effect of ET3 on these two NC derivatives was confirmed by the quantitative analysis of clones derived from individual NCC subjected to ET3: we found a large increase in the survival and proliferation of unipotent and bipotent precursors for glial cells and melanocytes, with no significant effect on multipotent cells generating neurons [13].
  • Lyt-1 T cells of mice treated with TNP-IgG can protect the adoptive contact sensitivity response of immune cells from the antigen-specific suppressive effect produced by the addition of antigen-specific TsF or Tsc [3].

Associations of Slc12a3 with chemical compounds

  • The chimera NCC, in which Met1-Gly354 of the SR Ca(2+)-ATPase were replaced with the corresponding portion of the Na+,K(+)-ATPase, lost the thapsigargin-sensitive Ca(2+)-ATPase activity seen in CCC and [n/c]CC [14].
  • Immunofluorescent detection of distal tubule marker proteins and ultrastructural analysis revealed that the early DCT, which physiologically lacks epithelial Na(+) (ENaC) and Ca(2+) (TRPV5) channels, was virtually absent in NCC-deficient mice [8].
  • In addition, plasma aldosterone levels were significantly elevated in NCC (-/-) mice even in the presence of a low-potassium diet [15].
  • Life and death of the distal nephron: WNK4 and NCC as major players [16].

Other interactions of Slc12a3


Analytical, diagnostic and therapeutic context of Slc12a3

  • To gain a better understanding of the role of NCC in sodium and fluid volume homeostasis and in the pathogenesis of Gitelman's syndrome, we used gene targeting to prepare an NCC-deficient mouse [1].
  • Western blot analysis revealed immunoreactive bands in all mutant TSCs that were undistinguishable from wild-type TSC [10].


  1. Phenotype resembling Gitelman's syndrome in mice lacking the apical Na+-Cl- cotransporter of the distal convoluted tubule. Schultheis, P.J., Lorenz, J.N., Meneton, P., Nieman, M.L., Riddle, T.M., Flagella, M., Duffy, J.J., Doetschman, T., Miller, M.L., Shull, G.E. J. Biol. Chem. (1998) [Pubmed]
  2. Estrogen enhances whereas tamoxifen retards development of Tsc mouse liver hemangioma: a tumor related to renal angiomyolipoma and pulmonary lymphangioleiomyomatosis. El-Hashemite, N., Walker, V., Kwiatkowski, D.J. Cancer Res. (2005) [Pubmed]
  3. Production of antigen-specific contrasuppressor cells and factor, and their use in augmentation of cell-mediated immunity. Ptak, W., Bereta, M., Marcinkiewicz, J., Gershon, R.K., Green, D.R. J. Immunol. (1984) [Pubmed]
  4. Divergent patterns of colonization and immune response elicited from two intestinal Lactobacillus strains that display similar properties in vitro. Ibnou-Zekri, N., Blum, S., Schiffrin, E.J., von der Weid, T. Infect. Immun. (2003) [Pubmed]
  5. WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion. Kahle, K.T., Wilson, F.H., Leng, Q., Lalioti, M.D., O'Connell, A.D., Dong, K., Rapson, A.K., MacGregor, G.G., Giebisch, G., Hebert, S.C., Lifton, R.P. Nat. Genet. (2003) [Pubmed]
  6. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. Nijenhuis, T., Vallon, V., van der Kemp, A.W., Loffing, J., Hoenderop, J.G., Bindels, R.J. J. Clin. Invest. (2005) [Pubmed]
  7. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. Yang, C.L., Angell, J., Mitchell, R., Ellison, D.H. J. Clin. Invest. (2003) [Pubmed]
  8. Altered renal distal tubule structure and renal Na(+) and Ca(2+) handling in a mouse model for Gitelman's syndrome. Loffing, J., Vallon, V., Loffing-Cueni, D., Aregger, F., Richter, K., Pietri, L., Bloch-Faure, M., Hoenderop, J.G., Shull, G.E., Meneton, P., Kaissling, B. J. Am. Soc. Nephrol. (2004) [Pubmed]
  9. WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis. Rinehart, J., Kahle, K.T., de Los Heros, P., Vazquez, N., Meade, P., Wilson, F.H., Hebert, S.C., Gimenez, I., Gamba, G., Lifton, R.P. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  10. Pathophysiology of functional mutations of the thiazide-sensitive Na-Cl cotransporter in Gitelman disease. Sabath, E., Meade, P., Berkman, J., de los Heros, P., Moreno, E., Bobadilla, N.A., Vázquez, N., Ellison, D.H., Gamba, G. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  11. 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]
  12. Human and murine phenotypes associated with defects in cation-chloride cotransport. Delpire, E., Mount, D.B. Annu. Rev. Physiol. (2002) [Pubmed]
  13. Endothelin 3 selectively promotes survival and proliferation of neural crest-derived glial and melanocytic precursors in vitro. Lahav, R., Dupin, E., Lecoin, L., Glavieux, C., Champeval, D., Ziller, C., Le Douarin, N.M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  14. The amino-terminal 200 amino acids of the plasma membrane Na+,K+-ATPase alpha subunit confer ouabain sensitivity on the sarcoplasmic reticulum Ca(2+)-ATPase. Ishii, T., Takeyasu, K. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  15. Hypokalemia in a mouse model of Gitelman's syndrome. Morris, R.G., Hoorn, E.J., Knepper, M.A. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  16. Life and death of the distal nephron: WNK4 and NCC as major players. Hadchouel, J., Jeunemaitre, X. Cell metabolism (2006) [Pubmed]
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