Electrogenic sodium bicarbonate cotransporter 1

Protein-coding gene in the species Homo sapiens

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]
Band	4q13.3	End	71,572,087 bp^[1]

Gene location (Mouse)

Chr.	Chromosome 5 (mouse)^[2]

Band	5\|5 E1	Start	89,034,345 bp^[2]
Band	5\|5 E1	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

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]

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.

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000080493 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000060961 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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.
^ 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.
^ ^a ^b "Entrez Gene: SLC4A4 solute carrier family 4, sodium bicarbonate cotransporter, member 4".
^ 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.
^ 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.
^ 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.
^ 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.

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.

Membrane proteins, carrier proteins: membrane transport proteins solute carrier (TC 2A)

By group

SLC1–10

(1):	high affinity glutamate and neutral amino-acid transporter SLC1A1 2 3 4 5 6 7
(2):	facilitative GLUT transporter SLC2A1 2 3 4 5 6 7 8 9 10 11 12 13 14
(3):	heavy subunits of heterodimeric amino-acid transporters SLC3A1 2
(4):	bicarbonate transporter SLC4A1 2 3 4 5 6 7 8 9 10 11
(5):	sodium glucose cotransporter SLC5A1 2 3 4 5 6 7 8 9 10 11 12
(6):	sodium- and chloride- dependent sodium:neurotransmitter symporters SLC6A1 SLC6A2 SLC6A3 SLC6A4 SLC6A5 SLC6A6 SLC6A7 SLC6A8 SLC6A9 SLC6A10 SLC6A11 SLC6A12 SLC6A13 SLC6A14 SLC6A15 SLC6A16 SLC6A17 SLC6A18 SLC6A19 SLC6A20
(7):	cationic amino-acid transporter/glycoprotein-associated SLC7A1 SLC7A2 SLC7A3 SLC7A4 glycoprotein-associated/light or catalytic subunits of heterodimeric amino-acid transporters SLC7A5 SLC7A6 SLC7A7 SLC7A8 SLC7A9 SLC7A10 SLC7A11 SLC7A13 SLC7A14
(8):	Na⁺/Ca²⁺ exchanger SLC8A1 SLC8A2 SLC8A3
(9):	Na⁺/H⁺ exchanger SLC9A1 SLC9A2 SLC9A3 SLC9A4 SLC9A5 SLC9A6 SLC9A7 SLC9A8 SLC9A9 SLC9A10 SLC9A11
(10):	sodium bile salt cotransport SLC10A1 SLC10A2 SLC10A3 SLC10A4 SLC10A5 SLC10A6 SLC10A7 10A1 10A2 10A3 10A7

SLC11–20

(11):	proton coupled metal ion transporter SLC11A1 SLC11A2 11A3
(12):	electroneutral cation-Cl cotransporter SLC12A1 SLC12A2 SLC12A3 SLC12A4 SLC12A5 SLC12A6 SLC12A7 SLC12A8 SLC12A9
(13):	human Na⁺-sulfate/carboxylate cotransporter SLC13A1 SLC13A2 SLC13A3 SLC13A4 SLC13A5
(14):	urea transporter SLC14A1 SLC14A2
(15):	proton oligopeptide cotransporter SLC15A1 SLC15A2 SLC15A3 SLC15A4
(16):	monocarboxylate transporter SLC16A1 SLC16A2 SLC16A3 SLC16A4 SLC16A5 SLC16A6 SLC16A7 SLC16A8 SLC16A9 SLC16A10 SLC16A11 SLC16A12 SLC16A13 SLC16A14
(17):	Vesicular glutamate transporter 1 SLC17A1 SLC17A2 SLC17A3 SLC17A4 SLC17A5 SLC17A6 SLC17A7 SLC17A8 SLC17A9
(18):	vesicular monoamine transporter SLC18A1 SLC18A2 SLC18A3
(19):	folate/thiamine transporter SLC19A1 SLC19A2 SLC19A3
(20):	type III Na⁺-phosphate cotransporter SLC20A1 SLC20A2

SLC21–30

(21):	Organic anion-transporting polypeptide SLCO1A2 SLCO1B1 SLCO1B3 SLCO1B4 SLCO1C1 SLCO2A1 SLCO2B1 SLCO3A1 SLCO4A1 SLCO4C1 SLCO5A1(SLCO6A1)
(22):	organic cation/anion/zwitterion transporter SLC22A1 SLC22A2 SLC22A3 SLC22A4 SLC22A5 SLC22A6 SLC22A7 SLC22A8 SLC22A9 SLC22A10 SLC22A11 SLC22A12 SLC22A13 SLC22A14 SLC22A15 SLC22A16 SLC22A17 SLC22A18 SLC22A19 SLC22A20
(23):	Na+-dependent ascorbic acid transporter SLC23A1 SLC23A2 SLC23A3 SLC23A4
(24):	Na⁺/(Ca²⁺-K⁺) exchanger SLC24A1 SLC24A2 SLC24A3 SLC24A4 SLC24A5 SLC24A6
(25):	mitochondrial carrier SLC25A1 SLC25A2 SLC25A3 SLC25A4 SLC25A5 SLC25A6 SLC25A7 SLC25A8 SLC25A9 SLC25A10 SLC25A11 SLC25A12 SLC25A13 SLC25A14 SLC25A15 SLC25A16 SLC25A17 SLC25A18 SLC25A19 SLC25A20 SLC25A21 SLC25A22 SLC25A23 SLC25A24 SLC25A25 SLC25A26 SLC25A27 SLC25A28 SLC25A29 SLC25A30 SLC25A31 SLC25A32 SLC25A33 SLC25A34 SLC25A35 SLC25A36 SLC25A37 SLC25A38 SLC25A39 SLC25A40 SLC25A41 SLC25A42 SLC25A43 SLC25A44 SLC25A45 SLC25A46
(26):	multifunctional anion exchanger SLC26A1 SLC26A2 SLC26A3 SLC26A4 SLC26A5 SLC26A6 SLC26A7 SLC26A8 SLC26A9 SLC26A10 SLC26A11
(27):	fatty acid transport proteins SLC27A1 SLC27A2 SLC27A3 SLC27A4 SLC27A5 SLC27A6
(28):	Na⁺-coupled nucleoside transport (SLC28A1 SLC28A2 SLC28A3
(29):	facilitative nucleoside transporter SLC29A1 SLC29A2 SLC29A3 SLC29A4
(30):	zinc efflux SLC30A1 SLC30A2 SLC30A3 SLC30A4 SLC30A5 SLC30A6 SLC30A7 SLC30A8 SLC30A9 SLC30A10

SLC31–40

(31):	copper transporter SLC31A1
(32):	Vesicular glutamate transporter 1 SLC32A1
(33):	Acetyl-CoA transporter SLC33A1
(34):	type II Na⁺-phosphate cotransporter SLC34A1 SLC34A2 SLC34A3
(35):	nucleoside-sugar transporter SLC35A1 SLC35A2 SLC35A3 SLC35A4 SLC35A5 SLC35B1 SLC35B2 SLC35B3 SLC35B4 SLC35C1 SLC35C2 SLC35D1 SLC35D2 SLC35D3 SLC35E1 SLC35E2 SLC35E3 SLC35E4
(36):	proton-coupled amino-acid transporter SLC36A1 SLC36A2 SLC36A3 SLC36A436A2
(37):	sugar-phosphate/phosphate exchanger SLC37A1 SLC37A2 SLC37A3 SLC37A4
(38):	System A & N, sodium-coupled neutral amino-acid transporter SLC38A1 SLC38A2 SLC38A3 SLC38A4 SLC38A5 SLC38A6 SLC38A10
(39):	metal ion transporter SLC39A1 SLC39A2 SLC39A3 SLC39A4 SLC39A5 SLC39A6 SLC39A7 SLC39A8 SLC39A9 SLC39A10 SLC39A11 SLC39A12 SLC39A13 SLC39A14
(40):	basolateral iron transporter SLC40A1

SLC41–48

(41):	Magnesium transporter E SLC41A1 SLC41A2 SLC41A3
(42):	Ammonia transporter RhAG RhBG RhCG
(43):	Na⁺-independent, system-L like amino-acid transporter SLC43A1 SLC43A2 SLC43A3
(44):	Choline-like transporter SLC44A1 SLC44A2 SLC44A3 SLC44A4 SLC44A5
(45):	Putative sugar transporter SLC45A1 SLC45A2 SLC54A3 SLC45A4
(46):	Folate transporter SLC46A1 SLC46A2
(47):	multidrug and toxin extrusion SLC47A1 SLC47A2
(48):	Heme transporter

SLCO1–4
O1A2 O1B1 O1B3 O2B1 O431 O4A1

Ion pumps

Symporter, Cotransporter	Na⁺/K⁺,Cl⁻ Na⁺/P_i3 Na⁺/Cl⁻ Na⁺/glucose Na⁺/I⁻ Cl⁻/K⁺ 4 5
Antiporter (exchanger)	Na⁺/H⁺ Na⁺/Ca²⁺ Na⁺/(Ca²⁺-K⁺) - Cl⁻/HCO⁻ ₃ (Band 3) Cl⁻-formate Cl⁻-oxalate