Gene Symbol: Slc4a4
Description: solute carrier family 4 member 4
Alias: HHNMC, HNBC1, KNBC, NBC2, Nbc1, Nbc4, PNBC, SLC4A5, electrogenic sodium bicarbonate cotransporter 1, NBC-like protein, Na(+)/HCO3(-) cotransporter, Na+HCO3- cotransporter 4, sodium bicarbonate cotransporter, solute carrier family 4 (anion exchanger), member 4, solute carrier family 4, sodium bicarbonate cotransporter, member 4
Species: rat
Products:     Slc4a4

Top Publications

  1. Abuladze N, Lee I, Newman D, Hwang J, Boorer K, Pushkin A, et al. Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter. J Biol Chem. 1998;273:17689-95 pubmed
    ..pNBC encodes a 1079-residue polypeptide that differs at the N terminus from the recently cloned human sodium bicarbonate cotransporter isolated from kidney (kNBC) (Burnham, C. E., Amlal, H., Wang, Z., Shull, G. E., and Soleimani, M...
  2. Romero M, Fong P, Berger U, Hediger M, Boron W. Cloning and functional expression of rNBC, an electrogenic Na(+)-HCO3- cotransporter from rat kidney. Am J Physiol. 1998;274:F425-32 pubmed
    ..Subsequent removal of Na+ in the presence of CO2/HCO3- causes a depolarization of > 50 mV and a concomitant decrease of pHi. Thus rNBC is in the same newly identified family of Na(+)-linked HCO3- transporters as is aNBC. ..
  3. Schrödl Häußel M, Theparambil S, Deitmer J, Roussa E. Regulation of functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), in mouse astrocytes. Glia. 2015;63:1226-39 pubmed publisher
    The electrogenic sodium bicarbonate cotransporter NBCe1 (SLC4A4) is expressed in many cell types and is a major regulator of intracellular, and extracellular pH...
  4. Barmeyer C, Ye J, Soroka C, Geibel P, Hingsammer L, Weitgasser L, et al. Identification of functionally distinct Na-HCO3 co-transporters in colon. PLoS ONE. 2013;8:e62864 pubmed publisher
    ..We also conclude that NBCn1C/D regulates HCO3-dependent HOE694-insensitive Na-HCO3 cotransport and plays a critical role in pHi regulation in colonic epithelial cells. ..
  5. Xu J, Wang Z, Barone S, Petrovic M, Amlal H, Conforti L, et al. Expression of the Na+-HCO-3 cotransporter NBC4 in rat kidney and characterization of a novel NBC4 variant. Am J Physiol Renal Physiol. 2003;284:F41-50 pubmed
    ..the published sequence. Xenopus laevis oocytes injected with the full-length NBC4e cRNA were compared with NBC1-expressing oocytes...
  6. Majumdar D, Maunsbach A, Shacka J, Williams J, Berger U, Schultz K, et al. Localization of electrogenic Na/bicarbonate cotransporter NBCe1 variants in rat brain. Neuroscience. 2008;155:818-32 pubmed publisher
    ..In summary, the B and C variants are the predominant NBCe1 variants in rat brain and exhibit different localization profiles. ..
  7. Roussa E, Nastainczyk W, Thevenod F. Differential expression of electrogenic NBC1 (SLC4A4) variants in rat kidney and pancreas. Biochem Biophys Res Commun. 2004;314:382-9 pubmed
    ..expression and localization of NH(2)-terminal variants of the electrogenic Na(+)-HCO(3)(-) co-transporter NBC1 (SLC4A4) in the rat kidney and pancreas...
  8. Burnham C, Flagella M, Wang Z, Amlal H, Shull G, Soleimani M. Cloning, renal distribution, and regulation of the rat Na+-HCO3- cotransporter. Am J Physiol. 1998;274:F1119-26 pubmed
    ..In the kidney, NBC-1 is expressed mainly in the proximal tubule, with traces found in medullary thick ascending limb and papilla. HCO3- loading decreased NBC-1 mRNA levels, which were unchanged either by metabolic acidosis or by CDA. ..
  9. Cao L, Xia C, Shi Z, Wang N, Gu Z, Yu L, et al. Na+/HCO3- cotransporter is expressed on ? and ? cells during rat pancreatic development. World J Gastroenterol. 2016;22:9525-9533 pubmed
    ..the expression and localization of the electrogenic Na+/HCO3- cotransporter (NBC1) in rat pancreas during development...

More Information


  1. Cooper D, Saxena N, Yang H, Lee H, Moring A, Lee A, et al. Molecular and functional characterization of the electroneutral Na/HCO3 cotransporter NBCn1 in rat hippocampal neurons. J Biol Chem. 2005;280:17823-30 pubmed
    ..We propose that NBCn1 in hippocampal neurons may affect neuronal activity by regulating local pH as well as steady-state inward currents at synapses. ..
  2. Nakamura M, Satoh N, Suzuki M, Kume H, Homma Y, Seki G, et al. Stimulatory effect of insulin on renal proximal tubule sodium transport is preserved in type 2 diabetes with nephropathy. Biochem Biophys Res Commun. 2015;461:154-8 pubmed publisher
    ..In addition to hypoglycemia, insulin-induced renal sodium retention might also play a role in increased cardiovascular risk associated with intensive glycemic control in type 2 diabetic patients with nephropathy. ..
  3. Bulur N, Virreira M, Soyfoo M, Louchami K, Delporte C, Perret J, et al. Expression of the electrogenic Na+-HCO3--cotransporter NBCe1 in tumoral insulin-producing BRIN-BD11 cells. Cell Physiol Biochem. 2009;24:187-92 pubmed publisher
    ..BRIN-BD11 cells, like normal pancreatic islet B-cells, express NBCe1, with predominance of the B variant of this electrogenic Na+-HCO3--cotransporter. ..
  4. Perry C, Quissell D, Reyland M, Grichtchenko I. Electrogenic NBCe1 (SLC4A4), but not electroneutral NBCn1 (SLC4A7), cotransporter undergoes cholinergic-stimulated endocytosis in salivary ParC5 cells. Am J Physiol Cell Physiol. 2008;295:C1385-98 pubmed publisher
    ..Stable association of NBCn1 at the membrane may facilitate constitutive uptake of HCO(3)(-) across the BLM, thus supporting HCO(3)(-) luminal secretion and/or maintaining acid-base homeostasis in stimulated cells. ..
  5. Brandes A, Oehlke O, Schümann A, Heidrich S, Thevenod F, Roussa E. Adaptive redistribution of NBCe1-A and NBCe1-B in rat kidney proximal tubule and striated ducts of salivary glands during acid-base disturbances. Am J Physiol Regul Integr Comp Physiol. 2007;293:R2400-11 pubmed
  6. Ogata T. Bicarbonate secretion by rat bile duct brush cells indicated by immunohistochemical localization of CFTR, anion exchanger AE2, Na+/HCO3 -cotransporter, carbonic anhydrase II, Na+/H+ exchangers NHE1 and NHE3, H+/K+-ATPase, and Na+/K+-ATPase. Med Mol Morphol. 2006;39:44-8 pubmed
    ..The immunoreactivity of most of these proteins was absent or weak in principal cells. These results strongly suggest that BCs are a significant source of HCO(3) (-) secretion. ..
  7. Suzuki M, Vaisbich M, Yamada H, Horita S, Li Y, Sekine T, et al. Functional analysis of a novel missense NBC1 mutation and of other mutations causing proximal renal tubular acidosis. Pflugers Arch. 2008;455:583-93 pubmed
    Mutations in the Na(+)-HCO(3)(-) cotransporter NBC1 cause severe proximal tubular acidosis (pRTA) associated with ocular abnormalities...
  8. Thevenod F, Roussa E, Schmitt B, Romero M. Cloning and immunolocalization of a rat pancreatic Na(+) bicarbonate cotransporter. Biochem Biophys Res Commun. 1999;264:291-8 pubmed
    ..This rpNBC is 99% identical to the longer, more common form of NBC [pNBC; 1079 amino acids (aa); 122 kDa in human heart, pancreas, prostate, and a minor clone in kidney]...
  9. Thornell I, Wu J, Liu X, Bevensee M. PIP2 hydrolysis stimulates the electrogenic Na+-bicarbonate cotransporter NBCe1-B and -C variants expressed in Xenopus laevis oocytes. J Physiol. 2012;590:5993-6011 pubmed publisher
  10. Sonalker P, Tofovic S, Jackson E. Increased expression of the sodium transporter BSC-1 in spontaneously hypertensive rats. J Pharmacol Exp Ther. 2004;311:1052-61 pubmed
    ..We conclude that increased expression of BSC-1, and to a lesser extent, aquaporin-2, ROMK-1, NHE-3, and NBC-1 may contribute to the pathogenesis of hypertension in the SHR. ..
  11. Ma S, Kang J, Bae E, Choi C, Lee J, Kim S, et al. Effects of volume depletion and NaHCO3 loading on the expression of Na+/H+ exchanger isoform 3, Na+: HCO3- cotransporter type 1 and nitric oxide synthase in rat kidney. Clin Exp Pharmacol Physiol. 2008;35:262-7 pubmed
    ..loading on the expression of Na(+)/H(+) exchanger isoform 3 (NHE3), Na(+) : HCO(3)(-) cotransporter type 1 (NBC1) and neuronal (n) and inducible (i) isoforms of nitric oxide synthase (NOS) were determined in rat kidney. 2...
  12. Yang D, Shcheynikov N, Zeng W, Ohana E, So I, Ando H, et al. IRBIT coordinates epithelial fluid and HCO3- secretion by stimulating the transporters pNBC1 and CFTR in the murine pancreatic duct. J Clin Invest. 2009;119:193-202 pubmed publisher
    ..These findings define IRBIT as a key coordinator of epithelial fluid and HCO3- secretion and may have implications to all CFTR-expressing epithelia and to cystic fibrosis...
  13. Monazzami A, Rajabi H, Ghrakhanlou R, Yari K, Rahimi Z. Modulation of oxidative and glycolytic skeletal muscle fibers Na+/H+ exchanger1 (NHE1) and Na+/HCO3- co-transporter1 (NBC1) genes and proteins expression in type 2 diabetic rat (Streptozotocin + high fat diet) following long term endurance training. Cell Mol Biol (Noisy-le-grand). 2017;63:11-18 pubmed publisher
    ..The aim of present study was to investigate the effects of endurance training on muscle NHE1 and NBC1 genes and proteins expression in type 2 diabetic rats. Male wistar rats (n=30), 4 weeks old and 95.7±10...
  14. Amlal H, Chen Q, Greeley T, Pavelic L, Soleimani M. Coordinated down-regulation of NBC-1 and NHE-3 in sodium and bicarbonate loading. Kidney Int. 2001;60:1824-36 pubmed
  15. Fukuda H, Hirata T, Nakamura N, Kato A, Kawahara K, Wakabayashi S, et al. Identification and properties of a novel variant of NBC4 (Na(+)/HCO(3)- co-transporter 4) that is predominantly expressed in the choroid plexus. Biochem J. 2013;450:179-87 pubmed publisher
    ..We found that a novel variant of the NBC4 [NBC4g/Slc4a5 (solute carrier family 4, sodium bicarbonate co-transporter, member 5)] is almost exclusively expressed in the ..
  16. Wang G, Li C, Kim S, Ring T, Wen J, Djurhuus J, et al. Ureter obstruction alters expression of renal acid-base transport proteins in rat kidney. Am J Physiol Renal Physiol. 2008;295:F497-506 pubmed publisher
    ..expression of the type 3 Na+/H+ exchanger (NHE3) in the cortex (21 +/- 4%), electrogenic Na+/HCO3- cotransporter (NBC1; 71 +/- 5%), type 1 bumetanide-sensitive Na+-K+-2Cl- cotransporter (NKCC2; 3 +/- 1%), electroneutral Na+/HCO3- ..
  17. Yamamoto T, Shirayama T, Sakatani T, Takahashi T, Tanaka H, Takamatsu T, et al. Enhanced activity of ventricular Na+-HCO3- cotransport in pressure overload hypertrophy. Am J Physiol Heart Circ Physiol. 2007;293:H1254-64 pubmed
    ..Real-time PCR analysis was used to quantitatively assess expression of NBC-encoding mRNA, including SLC4A4 (encoding electrogenic NBC, NBCe1) and SLC4A7 (electroneutral NBC, NBCn1)...
  18. Orlowski A, Ciancio M, Caldiz C, De Giusti V, Aiello E. Reduced sarcolemmal expression and function of the NBCe1 isoform of the Na?-HCO?? cotransporter in hypertrophied cardiomyocytes of spontaneously hypertensive rats: role of the renin-angiotensin system. Cardiovasc Res. 2014;101:211-9 pubmed publisher
    ..This is due to retained transporter protein units in early endosomes. Moreover, NBCn1 activity seems to be increased in the hypertrophic myocardium of SHR, compensating impaired function of NBCe1. ..
  19. Shirakabe K, Priori G, Yamada H, Ando H, Horita S, Fujita T, et al. IRBIT, an inositol 1,4,5-trisphosphate receptor-binding protein, specifically binds to and activates pancreas-type Na+/HCO3- cotransporter 1 (pNBC1). Proc Natl Acad Sci U S A. 2006;103:9542-7 pubmed identify the target molecules of IRBIT, and we succeeded in identifying Na(+)/HCO(3)(-) cotransporter 1 (NBC1) as an IRBIT binding protein...
  20. Wendel C, Becker H, Deitmer J. The sodium-bicarbonate cotransporter NBCe1 supports glutamine efflux via SNAT3 (SLC38A3) co-expressed in Xenopus oocytes. Pflugers Arch. 2008;455:885-93 pubmed
    ..A model is presented that attempts to explain the role of intracellular pH, bicarbonate transport, and buffering capacity mediated by NBCe1 for uptake and efflux of glutamine via SNAT3. ..
  21. Praetorius J, Kim Y, Bouzinova E, Frische S, Rojek A, Aalkjaer C, et al. NBCn1 is a basolateral Na+-HCO3- cotransporter in rat kidney inner medullary collecting ducts. Am J Physiol Renal Physiol. 2004;286:F903-12 pubmed
    ..In conclusion, NBCn1 is a basolateral Na(+)-HCO(3)(-) cotransporter of IMCD cells and is differentially regulated in IMCD and medullary thick ascending limb. ..
  22. Soyfoo M, Bulur N, Virreira M, Louchami K, Lybaert P, Crutzen R, et al. Expression of the electrogenic Na+-HCO3--cotransporters NBCe1-A and NBCe1-B in rat pancreatic islet cells. Endocrine. 2009;35:449-58 pubmed publisher
  23. Fantinelli J, Orlowski A, Aiello E, Mosca S. The electrogenic cardiac sodium bicarbonate co-transporter (NBCe1) contributes to the reperfusion injury. Cardiovasc Pathol. 2014;23:224-30 pubmed publisher
    ..Consistently, we have shown herein that the selective NBCe1 blockade with a-L3 exerted cardioprotection. This beneficial action strongly suggests that NBCe1 could be a potential target for the treatment of coronary disease. ..
  24. Jakobsen J, Odgaard E, Wang W, Elkjaer M, Nielsen S, Aalkjaer C, et al. Functional up-regulation of basolateral Na+-dependent HCO3- transporter NBCn1 in medullary thick ascending limb of K+-depleted rats. Pflugers Arch. 2004;448:571-8 pubmed
    ..They also indicate that it is the delivery of luminal NH(4)(+) rather than systemic changes of pH that determine the expression of NBCn1. ..
  25. Choi I, Hu L, Rojas J, Schmitt B, Boron W. Role of glycosylation in the renal electrogenic Na+-HCO3- cotransporter (NBCe1). Am J Physiol Renal Physiol. 2003;284:F1199-206 pubmed
  26. Kwon T, Fulton C, Wang W, Kurtz I, Frøkiaer J, Aalkjaer C, et al. Chronic metabolic acidosis upregulates rat kidney Na-HCO cotransporters NBCn1 and NBC3 but not NBC1. Am J Physiol Renal Physiol. 2002;282:F341-51 pubmed
    ..a marked increase in the abundance of NBCn1 in the mTAL and NBC3 in intercalated cells, whereas the abundance of NBC1 in the proximal tubule was not altered...
  27. Suzuki M, Van Paesschen W, Stalmans I, Horita S, Yamada H, Bergmans B, et al. Defective membrane expression of the Na(+)-HCO(3)(-) cotransporter NBCe1 is associated with familial migraine. Proc Natl Acad Sci U S A. 2010;107:15963-8 pubmed publisher
    Homozygous mutations in SLC4A4, encoding the electrogenic Na(+)-HCO(3)(-) cotransporter NBCe1, have been known to cause proximal renal tubular acidosis (pRTA) and ocular abnormalities...
  28. Ahn D, Chung J, Kim J, Kim K, Park Y. Inhibition of renal Na+/H+ exchange in cadmium-intoxicated rats. Toxicol Appl Pharmacol. 2005;204:91-8 pubmed
    ..The protein abundance of Na(+)-HCO(3)(-) cotransporter-1 (NBC1) in whole kidney membrane fractions was slightly attenuated, whereas that of the Na(+)-K(+)-ATPase alpha-subunit ..
  29. Igarashi T, Inatomi J, Sekine T, Cha S, Kanai Y, Kunimi M, et al. Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities. Nat Genet. 1999;23:264-6 pubmed
  30. Giffard R, Papadopoulos M, van Hooft J, Xu L, Giuffrida R, Monyer H. The electrogenic sodium bicarbonate cotransporter: developmental expression in rat brain and possible role in acid vulnerability. J Neurosci. 2000;20:1001-8 pubmed
    The electrogenic sodium bicarbonate cotransporter (NBC) is expressed in glial cells in the brain and plays an important role in the regulation of both intracellular and extracellular pH...
  31. Kim Y, Kwon T, Christensen B, Nielsen J, Wall S, Madsen K, et al. Altered expression of renal acid-base transporters in rats with lithium-induced NDI. Am J Physiol Renal Physiol. 2003;285:F1244-57 pubmed
    ..This is likely to represent direct or compensatory effects to increase the capacity for HCO3- reabsorption, NH4+ reabsorption, and proton secretion to prevent the development of systemic metabolic acidosis. ..
  32. Bulur N, Crutzen R, Malaisse W, Sener A, Beauwens R, Golstein P. Interaction between cAMP, volume?regulated anion channels and the Na+?HCO3??cotransporter, NBCe1, in the regulation of nutrient? and hypotonicity?induced insulin release from isolated rat pancreatic islets and tumoral insulin?producing BRIN?BD11 cell. Mol Med Rep. 2013;7:1666-72 pubmed publisher
    ..The omission of Na+ suppressed the secretory response to extracellular hypotonicity. The observations of the present study do not support the hypothesis of a major role for sAC in the regulation of insulin release. ..
  33. Choi I, Soo Yang H, Boron W. The electrogenicity of the rat sodium-bicarbonate cotransporter NBCe1 requires interactions among transmembrane segments of the transporter. J Physiol. 2007;578:131-42 pubmed
    ..Thus, these chimeras were electroneutral, as were two others consisting of NBCe1(Nt-L)/NBCn1(TM6-Ct) and NBCn1(Nt-L)/NBCe1(TM6-Ct). We propose that the electrogenicity of NBCe1 requires interactions between TM1-5 and TM6-13. ..
  34. De Giusti V, Orlowski A, Ciancio M, Espejo M, Gonano L, Caldiz C, et al. Aldosterone stimulates the cardiac sodium/bicarbonate cotransporter via activation of the g protein-coupled receptor gpr30. J Mol Cell Cardiol. 2015;89:260-7 pubmed publisher
    ..Pre-incubation of myocytes with wortmannin (PI3K-AKT pathway blocker) prevented Ald- or G1-induced NBC stimulation. In summary, Ald stimulates NBC by GPR30 activation, ROS production and AKT stimulation. ..
  35. Kristensen J, Kristensen M, Juel C. Expression of Na+/HCO3- co-transporter proteins (NBCs) in rat and human skeletal muscle. Acta Physiol Scand. 2004;182:69-76 pubmed the kidney/pancreas/heart isoform NBC1, whereas the other protein (approximately 200 kDa) is related to the NBC4 isoform. The two NBC proteins represent the electrogenic isoforms named NBCe1 and NBCe2...
  36. Sonalker P, Tofovic S, Bastacky S, Jackson E. Chronic noradrenaline increases renal expression of NHE-3, NBC-1, BSC-1 and aquaporin-2. Clin Exp Pharmacol Physiol. 2008;35:594-600 pubmed publisher
  37. Turban S, Beutler K, Morris R, Masilamani S, Fenton R, Knepper M, et al. Long-term regulation of proximal tubule acid-base transporter abundance by angiotensin II. Kidney Int. 2006;70:660-8 pubmed
    ..changes in Ang-II receptor occupation alter the abundance of the basolateral Na(+)/HCO(-)(3) cotransporter (NBC1) or the apical membrane type 3 Na(+)/H(+) exchanger (NHE3)...
  38. Orlowski A, De Giusti V, Morgan P, Aiello E, Alvarez B. Binding of carbonic anhydrase IX to extracellular loop 4 of the NBCe1 Na+/HCO3- cotransporter enhances NBCe1-mediated HCO3- influx in the rat heart. Am J Physiol Cell Physiol. 2012;303:C69-80 pubmed publisher
    ..CAIX and NBCe1 have been linked to tumorigenesis and cardiac cell growth, respectively. Thus inhibition of CA activity might be useful to prevent activation of NBCe1 under these pathological conditions. ..
  39. Thomas C, Bishop D, Moore Morris T, Mercier J. Effects of high-intensity training on MCT1, MCT4, and NBC expressions in rat skeletal muscles: influence of chronic metabolic alkalosis. Am J Physiol Endocrinol Metab. 2007;293:E916-22 pubmed, with or without induced metabolic alkalosis, on lactate transporter (MCT1 and MCT4) and sodium bicarbonate cotransporter (NBC) content in rat skeletal muscles...
  40. Orlowski A, De Giusti V, Ciancio M, Espejo M, Aiello E. The cardiac electrogenic sodium/bicarbonate cotransporter (NBCe1) is activated by aldosterone through the G protein-coupled receptor 30 (GPR 30). Channels (Austin). 2016;10:428-434 pubmed
    ..Using immunofluorescence and confocal microscopy analysis we showed in this work that both NBCe1 and GPR30 are localized in t-tubules. In conclusion, we have demonstrated that NBCe1 is the NBC isoform activated by Ald in the heart. ..