Electrogenic sodium bicarbonate cotransporter 1 explained

Electrogenic sodium bicarbonate cotransporter 1, sodium bicarbonate cotransporter is a membrane transport protein that in humans is encoded by the SLC4A4 gene.^{[1] [2]}

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]^[3]

Clinical significance

In the brain, the sodium bicarbonate transporter is predominantly expressed by astrocytes.^[4] They may participate in regulation of brain extracellular space pH.^[5] Some mutations in the gene have been associated with familial hemiplegic migraine.^[6] Other mutations disrupt kidney bicarbonate transport and cause proximal renal tubular acidosis.^[7]

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

Further reading

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

Notes and References

1. Burnham CE, Amlal H, Wang Z, Shull GE, Soleimani M . Cloning and functional expression of a human kidney Na+:HCO3- cotransporter . J Biol Chem . 272 . 31 . 19111–4 . Aug 1997 . 9235899 . 10.1074/jbc.272.31.19111 . free .
2. Abuladze N, Lee I, Newman D, Hwang J, Boorer K, Pushkin A, Kurtz I . Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter . J Biol Chem . 273 . 28 . 17689–95 . Aug 1998 . 9651366 . 10.1074/jbc.273.28.17689 . free .
3. Web site: Entrez Gene: SLC4A4 solute carrier family 4, sodium bicarbonate cotransporter, member 4.
4. Theparambil. Shefeeq M.. Hosford. Patrick S.. Ruminot. Iván. Kopach. Olga. Reynolds. James R.. Sandoval. Pamela Y.. Rusakov. Dmitri A.. Barros. L. Felipe. Gourine. Alexander V.. 2020-10-08. Astrocytes regulate brain extracellular pH via a neuronal activity-dependent bicarbonate shuttle. Nature Communications. en. 11. 1. 5073. 10.1038/s41467-020-18756-3. 33033238. 7545092. 2020NatCo..11.5073T. 2041-1723. free.
5. Theparambil. Shefeeq M.. Hosford. Patrick S.. Ruminot. Iván. Kopach. Olga. Reynolds. James R.. Sandoval. Pamela Y.. Rusakov. Dmitri A.. Barros. L. Felipe. Gourine. Alexander V.. 2020-10-08. Astrocytes regulate brain extracellular pH via a neuronal activity-dependent bicarbonate shuttle. Nature Communications. en. 11. 1. 5073. 10.1038/s41467-020-18756-3. 33033238. 7545092. 2020NatCo..11.5073T. 2041-1723. free.
6. 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 . 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 . September 2010 . 20798035 . 2936614 . 10.1073/pnas.1008705107 . free .
7. Zhu Q, Kao L, Azimov R, Newman D, Liu W, Pushkin A, Abuladze N, Kurtz I . Topological location and structural importance of the NBCe1-A residues mutated in proximal renal tubular acidosis . J. Biol. Chem. . 285 . 18 . 13416–26 . April 2010 . 20197274 . 2859501 . 10.1074/jbc.M109.093286 . free .