Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Physiol
2011 Feb 15;589Pt 4:877-90. doi: 10.1113/jphysiol.2010.198713.
Show Gene links
Show Anatomy links
Role of an extracellular loop in determining the stoichiometry of Na+-HCO₃⁻ cotransporters.
Chen LM
,
Liu Y
,
Boron WF
.
???displayArticle.abstract???
The Na+–HCO₃⁻ cotransporters (NBCs) of the solute carrier 4 family (SLC4) are critical for regulating pH in cells as well as in fluids such as blood and cerebrospinal fluid. Moreover, mutations and gene disruptions in NBC are linked to a wide range of pathologies. NBCe1 (SLC4A4) is electrogenic because it has an apparent Na+:HCO₃⁻ stoichiometry of 1:2 or 1:3, whereas NBCn1 (SLC4A7) is electroneutral because it has an apparent stoichiometry of 1:1. Because stoichiometry influences the effect of transport on membrane potential and vice versa, a central question is what structural features underlie electrogenicity versus electroneutrality. A previous study on rat NBCe1/n1 chimeras demonstrated that the structural elements determining the electrogenicity of NBCe1-A are located within the transmembrane domain, excluding the large third extracellular loop. In the present study we generated a series of chimeras of human NBCe1-A and human NBCn1-A. We found that replacing merely the predicted fourth extracellular loop (EL4) – containing 32 amino acid residues that include 7 prolines – of human NBCe1-A with EL4 of NBCn1-A creates an electroneutral NBC. The opposite switch converts an electroneutral construct to one with electrogenic properties. The introduction of an N-glycosylation site into EL4 confirms that at least a part of it is exposed to the extracellular fluid. We hypothesize that putative EL4 either contributes to the substrate-binding vestibule or indirectly influences substrate binding by interacting with one or more transmembrane segments, thereby controlling the nature of transport.
Abuladze,
Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter.
1998, Pubmed,
Xenbase
Abuladze,
Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter.
1998,
Pubmed
,
Xenbase
Ahmed,
Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2.
2009,
Pubmed
Bacconi,
Renouncing electroneutrality is not free of charge: switching on electrogenicity in a Na+-coupled phosphate cotransporter.
2005,
Pubmed
,
Xenbase
Bevensee,
An electrogenic Na(+)-HCO(-)(3) cotransporter (NBC) with a novel COOH-terminus, cloned from rat brain.
2000,
Pubmed
,
Xenbase
Bevensee,
Intracellular pH regulation in cultured astrocytes from rat hippocampus. II. Electrogenic Na/HCO3 cotransport.
1997,
Pubmed
Bok,
Blindness and auditory impairment caused by loss of the sodium bicarbonate cotransporter NBC3.
2003,
Pubmed
Boron,
Modular structure of sodium-coupled bicarbonate transporters.
2009,
Pubmed
Boron,
Intracellular pH transients in squid giant axons caused by CO2, NH3, and metabolic inhibitors.
1976,
Pubmed
Boron,
Active proton transport stimulated by CO2/HCO3-, blocked by cyanide.
1976,
Pubmed
Boron,
Intracellular pH regulation in the renal proximal tubule of the salamander. Basolateral HCO3- transport.
1983,
Pubmed
Bouzinova,
Na+-dependent HCO3- uptake into the rat choroid plexus epithelium is partially DIDS sensitive.
2005,
Pubmed
Chen,
Chronic continuous hypoxia decreases the expression of SLC4A7 (NBCn1) and SLC4A10 (NCBE) in mouse brain.
2007,
Pubmed
Chen,
Use of a new polyclonal antibody to study the distribution and glycosylation of the sodium-coupled bicarbonate transporter NCBE in rodent brain.
2008,
Pubmed
,
Xenbase
Chen,
Cloning and characterization of a zebrafish homologue of human AQP1: a bifunctional water and gas channel.
2010,
Pubmed
,
Xenbase
Choi,
The electrogenicity of the rat sodium-bicarbonate cotransporter NBCe1 requires interactions among transmembrane segments of the transporter.
2007,
Pubmed
,
Xenbase
Choi,
An electroneutral sodium/bicarbonate cotransporter NBCn1 and associated sodium channel.
2000,
Pubmed
,
Xenbase
Choi,
Role of glycosylation in the renal electrogenic Na+-HCO3- cotransporter (NBCe1).
2003,
Pubmed
,
Xenbase
Compton,
The 3-4 loop of an archaeal glutamate transporter homolog experiences ligand-induced structural changes and is essential for transport.
2010,
Pubmed
Cooper,
Molecular and functional characterization of the electroneutral Na/HCO3 cotransporter NBCn1 in rat hippocampal neurons.
2005,
Pubmed
,
Xenbase
Dinour,
A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects.
2004,
Pubmed
,
Xenbase
Fei,
Expression cloning of a mammalian proton-coupled oligopeptide transporter.
1994,
Pubmed
,
Xenbase
Fujinaga,
Topology of the membrane domain of human erythrocyte anion exchange protein, AE1.
1999,
Pubmed
Ghezzi,
Substrate interactions of the electroneutral Na+-coupled inorganic phosphate cotransporter (NaPi-IIc).
2009,
Pubmed
,
Xenbase
Grichtchenko,
Cloning, characterization, and chromosomal mapping of a human electroneutral Na(+)-driven Cl-HCO3 exchanger.
2001,
Pubmed
,
Xenbase
Gross,
The stoichiometry of the electrogenic sodium bicarbonate cotransporter pNBC1 in mouse pancreatic duct cells is 2 HCO(3)(-):1 Na(+).
2001,
Pubmed
Gross,
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.
2001,
Pubmed
Groves,
Role of N-glycosylation in the expression of human band 3-mediated anion transport.
1994,
Pubmed
,
Xenbase
Gurnett,
Disruption of sodium bicarbonate transporter SLC4A10 in a patient with complex partial epilepsy and mental retardation.
2008,
Pubmed
Hmani,
A novel locus for Usher syndrome type II, USH2B, maps to chromosome 3 at p23-24.2.
1999,
Pubmed
Horita,
Functional analysis of NBC1 mutants associated with proximal renal tubular acidosis and ocular abnormalities.
2005,
Pubmed
,
Xenbase
Igarashi,
Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities.
1999,
Pubmed
Igarashi,
Novel nonsense mutation in the Na+/HCO3- cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma.
2001,
Pubmed
Inatomi,
Mutational and functional analysis of SLC4A4 in a patient with proximal renal tubular acidosis.
2004,
Pubmed
,
Xenbase
Jacobs,
Mice with targeted Slc4a10 gene disruption have small brain ventricles and show reduced neuronal excitability.
2008,
Pubmed
Lauritzen,
NBCn1 and NHE1 expression and activity in DeltaNErbB2 receptor-expressing MCF-7 breast cancer cells: contributions to pHi regulation and chemotherapy resistance.
2010,
Pubmed
Lu,
Effect of human carbonic anhydrase II on the activity of the human electrogenic Na/HCO3 cotransporter NBCe1-A in Xenopus oocytes.
2006,
Pubmed
,
Xenbase
Lu,
Reversible and irreversible interactions of DIDS with the human electrogenic Na/HCO3 cotransporter NBCe1-A: role of lysines in the KKMIK motif of TM5.
2007,
Pubmed
,
Xenbase
Majumdar,
Localization of electrogenic Na/bicarbonate cotransporter NBCe1 variants in rat brain.
2008,
Pubmed
Marino,
Expression and distribution of the Na(+)-HCO(-)(3) cotransporter in human pancreas.
1999,
Pubmed
Musa-Aziz,
Using fluorometry and ion-sensitive microelectrodes to study the functional expression of heterologously-expressed ion channels and transporters in Xenopus oocytes.
2010,
Pubmed
,
Xenbase
Müller-Berger,
The renal Na-HCO3-cotransporter expressed in Xenopus laevis oocytes: change in stoichiometry in response to elevation of cytosolic Ca2+ concentration.
2001,
Pubmed
,
Xenbase
Parker,
Characterization of human SLC4A10 as an electroneutral Na/HCO3 cotransporter (NBCn2) with Cl- self-exchange activity.
2008,
Pubmed
,
Xenbase
Puntheeranurak,
Three surface subdomains form the vestibule of the Na+/glucose cotransporter SGLT1.
2007,
Pubmed
Pushkin,
SLC4 base (HCO3 -, CO3 2-) transporters: classification, function, structure, genetic diseases, and knockout models.
2006,
Pubmed
Pushkin,
Cloning, tissue distribution, genomic organization, and functional characterization of NBC3, a new member of the sodium bicarbonate cotransporter family.
1999,
Pubmed
,
Xenbase
Romero,
The SLC4 family of HCO 3 - transporters.
2004,
Pubmed
Romero,
Expression cloning and characterization of a renal electrogenic Na+/HCO3- cotransporter.
1997,
Pubmed
,
Xenbase
Romero,
Molecular pathophysiology of SLC4 bicarbonate transporters.
2005,
Pubmed
Sassani,
Functional characterization of NBC4: a new electrogenic sodium-bicarbonate cotransporter.
2002,
Pubmed
Sciortino,
Cation and voltage dependence of rat kidney electrogenic Na(+)-HCO(-)(3) cotransporter, rkNBC, expressed in oocytes.
1999,
Pubmed
,
Xenbase
Soleimani,
Stoichiometry of Na+-HCO-3 cotransport in basolateral membrane vesicles isolated from rabbit renal cortex.
1987,
Pubmed
Stewart,
Role of nonconserved charged residues of the AE2 transmembrane domain in regulation of anion exchange by pH.
2007,
Pubmed
,
Xenbase
Suzuki,
Defective membrane expression of the Na(+)-HCO(3)(-) cotransporter NBCe1 is associated with familial migraine.
2010,
Pubmed
,
Xenbase
Tamura,
Short external loops as potential substrate binding site of gamma-aminobutyric acid transporters.
1995,
Pubmed
,
Xenbase
Virkki,
Functional characterization of human NBC4 as an electrogenic Na+-HCO cotransporter (NBCe2).
2002,
Pubmed
,
Xenbase
Wang,
The Na+-driven Cl-/HCO3- exchanger. Cloning, tissue distribution, and functional characterization.
2000,
Pubmed
,
Xenbase
Whitfield,
Genetic effects on toxic and essential elements in humans: arsenic, cadmium, copper, lead, mercury, selenium, and zinc in erythrocytes.
2010,
Pubmed
Zhu,
Novel topology in C-terminal region of the human plasma membrane anion exchanger, AE1.
2003,
Pubmed
