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Gene Review

SLC4A4  -  solute carrier family 4 (sodium...

Homo sapiens

Synonyms: Electrogenic sodium bicarbonate cotransporter 1, HNBC1, KNBC, NBC, NBC1, ...
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Disease relevance of SLC4A4


Psychiatry related information on SLC4A4

  • These results have implications for understanding the role of kNBC1 in the pathophysiologic processes of pRTA associated with ocular abnormalities and mental retardation [6].
  • This study investigated the effects of pyridostigmine pretreatment, NBC protective gear, and heat-exercise exposure on psychomotor performance and subjective sensations in eight healthy male volunteers [7].

High impact information on SLC4A4

  • By immunological analysis of human and rat eyes, we demonstrate that both kidney type (kNBC-1) and pancreatic type (pNBC-1) transporters are present in the corneal endothelium, trabecular meshwork, ciliary epithelium, and lens epithelium [4].
  • In addition, up to 80% of amiloride-insensitive pH(i) recovery from acid load in the presence of HCO(3)(-)/CO(2) was inhibited by adenovirus-mediated transfer of a specific hammerhead ribozyme against NBC-1, consistent with a major role of NBC-1 in overall HCO(3)-transport by the lens epithelium [4].
  • These results indicate that the normal transport activity of NBC-1 is indispensable not only for the maintenance of corneal and lenticular transparency but also for the regulation of aqueous humor outflow [4].
  • Cloning and comparison of full-length rabbit with human gastrointestinal and kidney NBC1 subtype revealed a conserved protein kinase A consensus sequence in the cytoplasmic N-terminus of the gastrointestinal NBC1 [8].
  • Pancreatic bicarbonate secretion: role of CFTR and the sodium-bicarbonate cotransporter [9].

Chemical compound and disease context of SLC4A4

  • Mutations in the SLC4A4 gene cause an autosomal recessive proximal renal tubular acidosis (pRTA), a disease characterized by impaired ability of the proximal tubule to reabsorb HCO(3)(-) from the glomerular filtrate [10].
  • The Na(+)-HCO(3)(-) cotransporter (NBC) is also stimulated by intracellular acidification, and part of the benefit of angiotensin-converting enzyme inhibitors after myocardial infarction may be due to inhibition of the NBC [11].
  • In addition, we describe both the organ and nephron segment distributions and the regulation of NBC-1 mRNA under three models of pH stress: chloride-depletion alkalosis (CDA), metabolic acidosis, and bicarbonate loading [12].

Biological context of SLC4A4


Anatomical context of SLC4A4


Associations of SLC4A4 with chemical compounds

  • GFP was linked to the NH2 terminus of NBC1, and labeling was examined by confocal microscopy [21].
  • To address this question, cDNAs for wild-type kidney NBC1 and its mutants R510H and S427L were generated, fused in frame with NH(2) terminally tagged GFP, and transiently expressed in Madin-Darby canine kidney cells [22].
  • Critical glutamate, aspartate, lysine, arginine and histidine residues in ILs/ELs and TMs were detected that were essential for kNBC1-mediated Na(+)-dependent base transport [23].
  • In addition to shifting the stoichiometry, 8-Br-cAMP caused a significant increase in the 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS)-sensitive basolateral membrane conductance (GDS) of cells expressing pNBC1, but not kNBC1 [24].
  • NBC1 activity is stimulated by 10% CO2, however, the mechanism is poorly understood [25].

Physical interactions of SLC4A4

  • A significant correlation between the magnitude of CAII binding and kNBC1-mediated flux was shown [26].
  • We have identified extracellular regions of AE1 and NBC1 that directly interact with CAIV, to form a physical complex between the proteins [27].

Regulatory relationships of SLC4A4


Other interactions of SLC4A4


Analytical, diagnostic and therapeutic context of SLC4A4


  1. Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities. Igarashi, T., Inatomi, J., Sekine, T., Cha, S.H., Kanai, Y., Kunimi, M., Tsukamoto, K., Satoh, H., Shimadzu, M., Tozawa, F., Mori, T., Shiobara, M., Seki, G., Endou, H. Nat. Genet. (1999) [Pubmed]
  2. A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects. Dinour, D., Chang, M.H., Satoh, J., Smith, B.L., Angle, N., Knecht, A., Serban, I., Holtzman, E.J., Romero, M.F. J. Biol. Chem. (2004) [Pubmed]
  3. Localization of NBC-1 variants in human kidney and renal cell carcinoma. Yamada, H., Yamazaki, S., Moriyama, N., Hara, C., Horita, S., Enomoto, Y., Kudo, A., Kawakami, H., Tanaka, Y., Fujita, T., Seki, G. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  4. Molecular basis of ocular abnormalities associated with proximal renal tubular acidosis. Usui, T., Hara, M., Satoh, H., Moriyama, N., Kagaya, H., Amano, S., Oshika, T., Ishii, Y., Ibaraki, N., Hara, C., Kunimi, M., Noiri, E., Tsukamoto, K., Inatomi, J., Kawakami, H., Endou, H., Igarashi, T., Goto, A., Fujita, T., Araie, M., Seki, G. J. Clin. Invest. (2001) [Pubmed]
  5. 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]
  6. Novel nonsense mutation in the Na+/HCO3- cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma. Igarashi, T., Inatomi, J., Sekine, T., Seki, G., Shimadzu, M., Tozawa, F., Takeshima, Y., Takumi, T., Takahashi, T., Yoshikawa, N., Nakamura, H., Endou, H. J. Am. Soc. Nephrol. (2001) [Pubmed]
  7. Effects of heat-exercise stress, NBC clothing, and pyridostigmine treatment on psychomotor and subjective measures of performance. Arad, M., Varssano, D., Moran, D., Arnon, R., Vazina, A., Epstein, Y. Military medicine. (1992) [Pubmed]
  8. Role of Na(+)HCO(3)(-) cotransporter NBC1, Na(+)/H(+) exchanger NHE1, and carbonic anhydrase in rabbit duodenal bicarbonate secretion. Jacob, P., Christiani, S., Rossmann, H., Lamprecht, G., Vieillard-Baron, D., Müller, R., Gregor, M., Seidler, U. Gastroenterology (2000) [Pubmed]
  9. Pancreatic bicarbonate secretion: role of CFTR and the sodium-bicarbonate cotransporter. Whitcomb, D.C. Gastroenterology (1999) [Pubmed]
  10. The human NBCe1-A mutant R881C, associated with proximal renal tubular acidosis, retains function but is mistargeted in polarized renal epithelia. Toye, A.M., Parker, M.D., Daly, C.M., Lu, J., Virkki, L.V., Pelletier, M.F., Boron, W.F. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  11. Is timing everything? Therapeutic potential of modulators of cardiac Na(+) transporters. Doggrell, S.A., Hancox, J.C. Expert opinion on investigational drugs. (2003) [Pubmed]
  12. Cloning, renal distribution, and regulation of the rat Na+-HCO3- cotransporter. Burnham, C.E., Flagella, M., Wang, Z., Amlal, H., Shull, G.E., Soleimani, M. Am. J. Physiol. (1998) [Pubmed]
  13. Cloning, tissue distribution, genomic organization, and functional characterization of NBC3, a new member of the sodium bicarbonate cotransporter family. Pushkin, A., Abuladze, N., Lee, I., Newman, D., Hwang, J., Kurtz, I. J. Biol. Chem. (1999) [Pubmed]
  14. Proximal renal tubular acidosis and ocular pathology: a novel missense mutation in the gene (SLC4A4) for sodium bicarbonate cotransporter protein (NBCe1). Demirci, F.Y., Chang, M.H., Mah, T.S., Romero, M.F., Gorin, M.B. Mol. Vis. (2006) [Pubmed]
  15. Electrogenic Na+/HCO3- cotransporters: cloning and physiology. Romero, M.F., Boron, W.F. Annu. Rev. Physiol. (1999) [Pubmed]
  16. Voltage dependence of H+ buffering mediated by sodium bicarbonate cotransport expressed in Xenopus oocytes. Becker, H.M., Deitmer, J.W. J. Biol. Chem. (2004) [Pubmed]
  17. Phosphorylation of Ser(982) in the sodium bicarbonate cotransporter kNBC1 shifts the HCO(3)(-) : Na(+) stoichiometry from 3 : 1 to 2 : 1 in murine proximal tubule cells. Gross, E., Hawkins, K., Pushkin, A., Sassani, P., Dukkipati, R., Abuladze, N., Hopfer, U., Kurtz, I. J. Physiol. (Lond.) (2001) [Pubmed]
  18. Sodium coupled bicarbonate transporters in the kidney, an update. Aalkjaer, C., Frische, S., Leipziger, J., Nielsen, S., Praetorius, J. Acta Physiol. Scand. (2004) [Pubmed]
  19. Direct extracellular interaction between carbonic anhydrase IV and the human NBC1 sodium/bicarbonate co-transporter. Alvarez, B.V., Loiselle, F.B., Supuran, C.T., Schwartz, G.J., Casey, J.R. Biochemistry (2003) [Pubmed]
  20. Na+:HCO(3-) cotransporters (NBC): cloning and characterization. Soleimani, M., Burnham, C.E. J. Membr. Biol. (2001) [Pubmed]
  21. Identification of a carboxyl-terminal motif essential for the targeting of Na+-HCO-3 cotransporter NBC1 to the basolateral membrane. Li, H.C., Worrell, R.T., Matthews, J.B., Husseinzadeh, H., Neumeier, L., Petrovic, S., Conforti, L., Soleimani, M. J. Biol. Chem. (2004) [Pubmed]
  22. Missense mutations in Na+:HCO3- cotransporter NBC1 show abnormal trafficking in polarized kidney cells: a basis of proximal renal tubular acidosis. Li, H.C., Szigligeti, P., Worrell, R.T., Matthews, J.B., Conforti, L., Soleimani, M. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  23. Critical amino acid residues involved in the electrogenic sodium-bicarbonate cotransporter kNBC1-mediated transport. Abuladze, N., Azimov, R., Newman, D., Sassani, P., Liu, W., Tatishchev, S., Pushkin, A., Kurtz, I. J. Physiol. (Lond.) (2005) [Pubmed]
  24. Phosphorylation-induced modulation of pNBC1 function: distinct roles for the amino- and carboxy-termini. Gross, E., Fedotoff, O., Pushkin, A., Abuladze, N., Newman, D., Kurtz, I. J. Physiol. (Lond.) (2003) [Pubmed]
  25. Regulation of renal Na+/HCO3- cotransporter stimulation by CO2: role of phosphorylation, exocytosis and protein synthesis. Espiritu, D.J., Yang, V.L., Bernardo, A.A., Arruda, J.A. J. Membr. Biol. (2004) [Pubmed]
  26. Molecular mechanism of kNBC1-carbonic anhydrase II interaction in proximal tubule cells. Pushkin, A., Abuladze, N., Gross, E., Newman, D., Tatishchev, S., Lee, I., Fedotoff, O., Bondar, G., Azimov, R., Ngyuen, M., Kurtz, I. J. Physiol. (Lond.) (2004) [Pubmed]
  27. The bicarbonate transport metabolon. McMurtrie, H.L., Cleary, H.J., Alvarez, B.V., Loiselle, F.B., Sterling, D., Morgan, P.E., Johnson, D.E., Casey, J.R. Journal of enzyme inhibition and medicinal chemistry. (2004) [Pubmed]
  28. Physiologic and molecular aspects of the Na+:HCO3- cotransporter in health and disease processes. Soleimani, M., Burnham, C.E. Kidney Int. (2000) [Pubmed]
  29. Mouse Na+: HCO3- cotransporter isoform NBC-3 (kNBC-3): cloning, expression, and renal distribution. Wang, Z., Conforti, L., Petrovic, S., Amlal, H., Burnham, C.E., Soleimani, M. Kidney Int. (2001) [Pubmed]
  30. Assignment of the human solute carrier family 4, sodium bicarbonate cotransporter-like, member 10 gene (SLC4A10) to 2q23-->q24 by in situ hybridization and radiation hybrid mapping. Yano, H., Wang, C., Yamashita, S., Yokoyama, Y., Yokoi, N., Seino, S. Cytogenet. Cell Genet. (2000) [Pubmed]
  31. Functional characterization of NBC4: a new electrogenic sodium-bicarbonate cotransporter. Sassani, P., Pushkin, A., Gross, E., Gomer, A., Abuladze, N., Dukkipati, R., Carpenito, G., Kurtz, I. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  32. Molecular cloning of a new sodium bicarbonate cotransporter cDNA from human retina. Ishibashi, K., Sasaki, S., Marumo, F. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  33. Characterization of Na+/HCO-3 cotransporter isoform NBC-3. Amlal, H., Burnham, C.E., Soleimani, M. Am. J. Physiol. (1999) [Pubmed]
  34. Identification and cloning of the Na/HCO(3-) cotransporter (NBC) in human corneal endothelium. Sun, X.C., Bonanno, J.A. Exp. Eye Res. (2003) [Pubmed]
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