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Gene Review

Slc4a4  -  solute carrier family 4 (anion exchanger),...

Mus musculus

Synonyms: AI835705, Electrogenic sodium bicarbonate cotransporter 1, NBC, NBC1, Na(+)/HCO3(-) cotransporter, ...
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Disease relevance of Slc4a4


High impact information on Slc4a4

  • To test the hypothesis that NBC1 plays a role in transepithelial HCO(3)(-) secretion in the intestinal tract, null mutant (NBC1(-/-)) mice were prepared by targeted disruption of its gene (Slc4a4) [2].
  • Fluorescence correlation spectroscopy analysis of CAII microinjected into OLs reveals freely diffusing protein throughout the cell as well as protein associated predominantly with NHE in the perikaryon and predominantly with NBC in the dendrites [3].
  • Functional and immunocytochemical localization of these activities in the perfused duct indicated that pNBC1 probably mediates the DIDS-sensitive/EIPA-insensitive transport in the basolateral membrane, and splice variants of NBC3 probably mediate the DIDS-insensitive/EIPA-sensitive NBC activity in the LM of duct and acinar cells [4].
  • NBC was phosphorylated in BSC-1 cells, but its phosphorylation was not increased by cAMP nor was immunoprecipitated NBC phosphorylated by PKA in vitro [5].
  • Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter [6].

Biological context of Slc4a4


Anatomical context of Slc4a4

  • The stoichiometry of the electrogenic sodium bicarbonate cotransporter pNBC1 in mouse pancreatic duct cells is 2 HCO(3)(-):1 Na(+) [10].
  • Molecular cloning and functional expression of a sodium bicarbonate cotransporter from guinea-pig parotid glands [11].
  • Expression of NBC in 3T3 cells that do not normally express this transporter rendered them vulnerable to acid injury [12].
  • Ionic substitution studies and inhibition of injury by 4, 4'-di-isothiocyanostilbene-2,2'-disulfonic acid suggest that NBC is involved in astrocyte vulnerability to acidic injury [12].
  • Thus the mechanisms of fluid and anion secretion in salivary acinar cells may be different between PAR and SMG, and, because NBC was detected in acinar and duct cells, it may play a more important role in transport of HCO(-)(3) by rat salivary duct cells than previously believed [13].

Associations of Slc4a4 with chemical compounds

  • These studies establish the existence of an intracellular HCO(3)(-) concentration- and cell volume-independent activation of colonic NBC by an increase in intracellular cAMP [14].
  • Finally, the addition of arachidonic acid inhibited the NBC activity similarly in WT and AT(1A) KO, suggesting that the inhibitory pathway involving P-450 metabolites is preserved in AT(1A) KO [15].

Other interactions of Slc4a4

  • Both NBC1 and NBCn1 were localized to the basolateral membrane of proximal duodenal villus cells, whereas the crypt cells did not label with the anti-NBC antibodies [16].
  • Sodium/hydrogen exchanger isoform 1 (NHE1) and sodium-bicarbonate cotransporter expression were decreased in all regions of the CNS but especially so in the cerebellum [7].
  • 1. The pancreatic variant of the sodium bicarbonate cotransporter, pNBC1, mediates basolateral bicarbonate influx in the exocrine pancreas by coupling the transport of bicarbonate to that of sodium, with a 2 HCO3-:1 Na+ stoichiometry [17].

Analytical, diagnostic and therapeutic context of Slc4a4


  1. Time course of auditory impairment in mice lacking the electroneutral sodium bicarbonate cotransporter NBC3 (slc4a7). Lopez, I.A., Acuna, D., Galbraith, G., Bok, D., Ishiyama, A., Liu, W., Kurtz, I. Brain Res. Dev. Brain Res. (2005) [Pubmed]
  2. Colonic Anion Secretory Defects and Metabolic Acidosis in Mice Lacking the NBC1 Formula Cotransporter. Gawenis, L.R., Bradford, E.M., Prasad, V., Lorenz, J.N., Simpson, J.E., Clarke, L.L., Woo, A.L., Grisham, C., Sanford, L.P., Doetschman, T., Miller, M.L., Shull, G.E. J. Biol. Chem. (2007) [Pubmed]
  3. pH microdomains in oligodendrocytes. Ro, H.A., Carson, J.H. J. Biol. Chem. (2004) [Pubmed]
  4. 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]
  5. Essential role for NHERF in cAMP-mediated inhibition of the Na+-HCO3- co-transporter in BSC-1 cells. Weinman, E.J., Evangelista, C.M., Steplock, D., Liu, M.Z., Shenolikar, S., Bernardo, A. J. Biol. Chem. (2001) [Pubmed]
  6. Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter. Abuladze, N., Lee, I., Newman, D., Hwang, J., Boorer, K., Pushkin, A., Kurtz, I. J. Biol. Chem. (1998) [Pubmed]
  7. Chronic intermittent hypoxia decreases the expression of Na/H exchangers and HCO3-dependent transporters in mouse CNS. Douglas, R.M., Xue, J., Chen, J.Y., Haddad, C.G., Alper, S.L., Haddad, G.G. J. Appl. Physiol. (2003) [Pubmed]
  8. Molecular and functional evidence for a Na(+)-HCO3(-)-cotransporter in sheep ruminal epithelium. Huhn, K., Müller, F., Honscha, K.U., Pfannkuche, H., Gäbel, G. J. Comp. Physiol. B, Biochem. Syst. Environ. Physiol. (2003) [Pubmed]
  9. Regulation of hypothalamic gene expression by glucocorticoid: implications for energy homeostasis. Nishida, Y., Yoshioka, M., St-Amand, J. Physiol. Genomics (2006) [Pubmed]
  10. The stoichiometry of the electrogenic sodium bicarbonate cotransporter pNBC1 in mouse pancreatic duct cells is 2 HCO(3)(-):1 Na(+). Gross, E., Abuladze, N., Pushkin, A., Kurtz, I., Cotton, C.U. J. Physiol. (Lond.) (2001) [Pubmed]
  11. Molecular cloning and functional expression of a sodium bicarbonate cotransporter from guinea-pig parotid glands. Koo, N.Y., Li, J., Hwang, S.M., Choi, S.Y., Lee, S.J., Oh, S.B., Kim, J.S., Lee, J.H., Park, K. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  12. The electrogenic sodium bicarbonate cotransporter: developmental expression in rat brain and possible role in acid vulnerability. Giffard, R.G., Papadopoulos, M.C., van Hooft, J.A., Xu, L., Giuffrida, R., Monyer, H. J. Neurosci. (2000) [Pubmed]
  13. Immunolocalization of anion exchanger AE2 and Na(+)-HCO(-)(3) cotransporter in rat parotid and submandibular glands. Roussa, E., Romero, M.F., Schmitt, B.M., Boron, W.F., Alper, S.L., Thévenod, F. Am. J. Physiol. (1999) [Pubmed]
  14. cAMP-mediated regulation of murine intestinal/pancreatic Na+/HCO3- cotransporter subtype pNBC1. Bachmann, O., Rossmann, H., Berger, U.V., Colledge, W.H., Ratcliff, R., Evans, M.J., Gregor, M., Seidler, U. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) [Pubmed]
  15. Biphasic regulation of Na+-HCO3- cotransporter by angiotensin II type 1A receptor. Horita, S., Zheng, Y., Hara, C., Yamada, H., Kunimi, M., Taniguchi, S., Uwatoko, S., Sugaya, T., Goto, A., Fujita, T., Seki, G. Hypertension (2002) [Pubmed]
  16. Molecular and functional evidence for electrogenic and electroneutral Na(+)-HCO(3)(-) cotransporters in murine duodenum. Praetorius, J., Hager, H., Nielsen, S., Aalkjaer, C., Friis, U.G., Ainsworth, M.A., Johansen, T. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  17. The stoichiometry of the electrogenic sodium bicarbonate cotransporter NBC1 is cell-type dependent. Gross, E., Hawkins, K., Abuladze, N., Pushkin, A., Cotton, C.U., Hopfer, U., Kurtz, I. J. Physiol. (Lond.) (2001) [Pubmed]
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