Electrogenic sodium bicarbonate cotransporter 1

Electrogenic sodium bicarbonate cotransporter 1, sodium bicarbonate cotransporter is a membrane transport protein that in humans is encoded by the SLC4A4 gene.^[5][6][7]

SLC4A4
Identifiers
Aliases	SLC4A4, HNBC1, KNBC, NBC1, NBC2, NBCe1-A, SLC4A5, hhNMC, pNBC, kNBC1, solute carrier family 4 member 4
External IDs	OMIM: 603345; MGI: 1927555; HomoloGene: 55776; GeneCards: SLC4A4; OMA:SLC4A4 - orthologs
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4q13.3 Start 71,186,757 bp[1] End 71,572,087 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5|5 E1 Start 89,034,345 bp[2] End 89,387,512 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in jejunal mucosa external globus pallidus mucosa of sigmoid colon pancreatic ductal cell internal globus pallidus kidney tubule body of pancreas dorsal motor nucleus of vagus nerve duodenum bronchial epithelial cell Top expressed in ciliary body cerebellar vermis deep cerebellar nuclei human kidney lobe of cerebellum globus pallidus dorsal tegmental nucleus right kidney medial vestibular nucleus iris More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transporter activity anion transmembrane transporter activity protein binding symporter activity inorganic anion exchanger activity sodium:bicarbonate symporter activity identical protein binding Cellular component integral component of membrane plasma membrane basolateral plasma membrane integral component of plasma membrane extracellular exosome membrane Biological process bicarbonate transport anion transmembrane transport anion transport sodium ion transport sodium ion transmembrane transport ion transport inorganic anion transport regulation of intracellular pH transmembrane transport transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 8671 54403 Ensembl ENSG00000080493 ENSMUSG00000060961 UniProt Q9Y6R1 O88343 RefSeq (mRNA) NM_001098484 NM_001134742 NM_003759 NM_001136260 NM_001197147 NM_018760 NM_001359211 NM_001359212 NM_001359213 RefSeq (protein) NP_001091954 NP_001128214 NP_003750 NP_001129732 NP_001184076 NP_061230 NP_001346140 NP_001346141 NP_001346142 Location (UCSC) Chr 4: 71.19 – 71.57 Mb Chr 5: 89.03 – 89.39 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Function

Sodium bicarbonate cotransporters (NBCs) mediate the coupled movement of sodium and bicarbonate ions across the plasma membrane of many cells. This is an electrogenic process with an apparent stoichiometry of 3 bicarbonate ions per sodium ion. Sodium bicarbonate co-transport is involved in bicarbonate secretion/absorption and intracellular pH regulation. Romero and Boron (1999) reviewed NBCs. Soleimani and Burnham (2000) reviewed NBCs and their regulation in physiologic and pathophysiologic states.[supplied by OMIM]^[7]

Clinical significance

In the brain, the sodium bicarbonate transporter is predominantly expressed by astrocytes.^[8] They may participate in regulation of brain extracellular space pH.^[9] Some mutations in the gene have been associated with familial hemiplegic migraine.^[10] Other mutations disrupt kidney bicarbonate transport and cause proximal renal tubular acidosis.^[11]

Splice variants

NBCe1-A aka kNBC1 (mainly expressed in the kidney)

NBCe1-B aka pNBC1 (expressed in the pancreas and elsewhere)

NBCe1-C (expressed in the brain)

Distribution

The renal SLC4A4 gene product NBCe1-A is specifically expressed in the basolateral membranes of proximal tubule epithelia.

See also

• Solute carrier family

References

1. GRCh38: Ensembl release 89: ENSG00000080493 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000060961 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Burnham CE, Amlal H, Wang Z, Shull GE, Soleimani M (Aug 1997). "Cloning and functional expression of a human kidney Na+:HCO3- cotransporter". J Biol Chem. 272 (31): 19111–4. doi:10.1074/jbc.272.31.19111. PMID 9235899.
6. Abuladze N, Lee I, Newman D, Hwang J, Boorer K, Pushkin A, Kurtz I (Aug 1998). "Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter". J Biol Chem. 273 (28): 17689–95. doi:10.1074/jbc.273.28.17689. PMID 9651366.
7. "Entrez Gene: SLC4A4 solute carrier family 4, sodium bicarbonate cotransporter, member 4".
8. Theparambil SM, Hosford PS, Ruminot I, Kopach O, Reynolds JR, Sandoval PY, Rusakov DA, Barros LF, Gourine AV (2020-10-08). "Astrocytes regulate brain extracellular pH via a neuronal activity-dependent bicarbonate shuttle". Nature Communications. 11 (1): 5073. Bibcode:2020NatCo..11.5073T. doi:10.1038/s41467-020-18756-3. ISSN 2041-1723. PMC 7545092. PMID 33033238.
9. Theparambil SM, Hosford PS, Ruminot I, Kopach O, Reynolds JR, Sandoval PY, Rusakov DA, Barros LF, Gourine AV (2020-10-08). "Astrocytes regulate brain extracellular pH via a neuronal activity-dependent bicarbonate shuttle". Nature Communications. 11 (1): 5073. Bibcode:2020NatCo..11.5073T. doi:10.1038/s41467-020-18756-3. ISSN 2041-1723. PMC 7545092. PMID 33033238.
10. Suzuki M, Van Paesschen W, Stalmans I, Horita S, Yamada H, Bergmans BA, Legius E, Riant F, De Jonghe P, Li Y, Sekine T, Igarashi T, Fujimoto I, Mikoshiba K, Shimadzu M, Shiohara M, Braverman N, Al-Gazali L, Fujita T, Seki G (September 2010). "Defective membrane expression of the Na(+)-HCO(3)(-) cotransporter NBCe1 is associated with familial migraine". Proc. Natl. Acad. Sci. U.S.A. 107 (36): 15963–8. doi:10.1073/pnas.1008705107. PMC 2936614. PMID 20798035.
11. Zhu Q, Kao L, Azimov R, Newman D, Liu W, Pushkin A, Abuladze N, Kurtz I (April 2010). "Topological location and structural importance of the NBCe1-A residues mutated in proximal renal tubular acidosis". J. Biol. Chem. 285 (18): 13416–26. doi:10.1074/jbc.M109.093286. PMC 2859501. PMID 20197274.

Further reading

• Romero MF, Boron WF (1999). "Electrogenic Na+/HCO3- cotransporters: cloning and physiology". Annu. Rev. Physiol. 61: 699–723. doi:10.1146/annurev.physiol.61.1.699. PMID 10099707.
• Soleimani M, Burnham CE (2000). "Physiologic and molecular aspects of the Na+:HCO3- cotransporter in health and disease processes". Kidney Int. 57 (2): 371–84. doi:10.1046/j.1523-1755.2000.00857.x. PMID 10652014.
• Choi I, Romero MF, Khandoudi N, et al. (1999). "Cloning and characterization of a human electrogenic Na+-HCO-3 cotransporter isoform (hhNBC)". Am. J. Physiol. 276 (3 Pt 1): C576–84. doi:10.1152/ajpcell.1999.276.3.C576. PMID 10069984. S2CID 23345395.
• Igarashi T, Inatomi J, Sekine T, et al. (1999). "Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities". Nat. Genet. 23 (3): 264–6. doi:10.1038/15440. PMID 10545938. S2CID 547845.
• Pushkin A, Yip KP, Clark I, et al. (2000). "NBC3 expression in rabbit collecting duct: colocalization with vacuolar H+-ATPase". Am. J. Physiol. 277 (6 Pt 2): F974–81. doi:10.1152/ajprenal.1999.277.6.F974. PMID 10600945. S2CID 4457223.
• Park K, Hurley PT, Roussa E, et al. (2002). "Expression of a sodium bicarbonate cotransporter in human parotid salivary glands". Arch. Oral Biol. 47 (1): 1–9. doi:10.1016/S0003-9969(01)00098-X. PMID 11743927.
• Gross E, Hawkins K, Pushkin A, et al. (2002). "Phosphorylation of Ser982 in the sodium bicarbonate cotransporter kNBC1 shifts the HCO3−: Na+ stoichiometry from 3:1 to 2:1 in murine proximal tubule cells". J. Physiol. 537 (Pt 3): 659–65. doi:10.1113/jphysiol.2001.012956. PMC 2278987. PMID 11744745.
• Gross E, Pushkin A, Abuladze N, et al. (2003). "Regulation of the sodium bicarbonate cotransporter kNBC1 function: role of Asp986, Asp988 and kNBC1-carbonic anhydrase II binding". J. Physiol. 544 (Pt 3): 679–85. doi:10.1113/jphysiol.2002.029777. PMC 2290621. PMID 12411514.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Tatishchev S, Abuladze N, Pushkin A, et al. (2003). "Identification of membrane topography of the electrogenic sodium bicarbonate cotransporter pNBC1 by in vitro transcription/translation". Biochemistry. 42 (3): 755–65. doi:10.1021/bi026826q. PMID 12534288.
• Gross E, Fedotoff O, Pushkin A, et al. (2004). "Phosphorylation-induced modulation of pNBC1 function: distinct roles for the amino- and carboxy-termini". J. Physiol. 549 (Pt 3): 673–82. doi:10.1113/jphysiol.2003.042226. PMC 2342979. PMID 12730338.
• Sun XC, Bonanno JA (2003). "Identification and cloning of the Na/HCO(3-) cotransporter (NBC) in human corneal endothelium". Exp. Eye Res. 77 (3): 287–95. doi:10.1016/S0014-4835(03)00150-7. PMC 4106483. PMID 12907161.
• Yamada H, Yamazaki S, Moriyama N, et al. (2003). "Localization of NBC-1 variants in human kidney and renal cell carcinoma". Biochem. Biophys. Res. Commun. 310 (4): 1213–8. doi:10.1016/j.bbrc.2003.09.147. PMID 14559244.
• Alvarez BV, Loiselle FB, Supuran CT, et al. (2003). "Direct extracellular interaction between carbonic anhydrase IV and the human NBC1 sodium/bicarbonate co-transporter". Biochemistry. 42 (42): 12321–9. doi:10.1021/bi0353124. PMID 14567693.
• Becker HM, Deitmer JW (2004). "Voltage dependence of H+ buffering mediated by sodium bicarbonate cotransport expressed in Xenopus oocytes". J. Biol. Chem. 279 (27): 28057–62. doi:10.1074/jbc.M402401200. PMID 15123668.
• Pushkin A, Abuladze N, Gross E, et al. (2005). "Molecular mechanism of kNBC1—carbonic anhydrase II interaction in proximal tubule cells". J. Physiol. 559 (Pt 1): 55–65. doi:10.1113/jphysiol.2004.065110. PMC 1665076. PMID 15218065.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.