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J Am Soc Nephrol
2023 Jan 01;341:40-54. doi: 10.1681/ASN.2022030289.
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Distinguishing among HCO 3- , CO 3= , and H + as Substrates of Proteins That Appear To Be "Bicarbonate" Transporters.
Lee SK
,
Occhipinti R
,
Moss FJ
,
Parker MD
,
Grichtchenko II
,
Boron WF
.
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BACKGROUND: Differentiating among HCO 3- , CO 3= , and H + movements across membranes has long seemed impossible. We now seek to discriminate unambiguously among three alternate mechanisms: the inward flux of 2 HCO 3- (mechanism 1), the inward flux of 1 CO 3= (mechanism 2), and the CO 2 /HCO 3- -stimulated outward flux of 2 H + (mechanism 3).
METHODS: As a test case, we use electrophysiology and heterologous expression in Xenopus oocytes to examine SLC4 family members that appear to transport "bicarbonate" ("HCO 3- ").
RESULTS: First, we note that cell-surface carbonic anhydrase should catalyze the forward reaction CO 2 +OH - →HCO 3- if HCO 3- is the substrate; if it is not, the reverse reaction should occur. Monitoring changes in cell-surface pH ( Δ pH S ) with or without cell-surface carbonic anhydrase, we find that the presumed Cl-"HCO 3 " exchanger AE1 (SLC4A1) does indeed transport HCO 3- (mechanism 1) as long supposed, whereas the electrogenic Na/"HCO 3 " cotransporter NBCe1 (SLC4A4) and the electroneutral Na + -driven Cl-"HCO 3 " exchanger NDCBE (SLC4A8) do not. Second, we use mathematical simulations to show that each of the three mechanisms generates unique quantities of H + at the cell surface (measured as Δ pH S ) per charge transported (measured as change in membrane current, ΔIm ). Calibrating ΔpH S /Δ Im in oocytes expressing the H + channel H V 1, we find that our NBCe1 data align closely with predictions of CO 3= transport (mechanism 2), while ruling out HCO 3- (mechanism 1) and CO 2 /HCO 3- -stimulated H + transport (mechanism 3).
CONCLUSIONS: Our surface chemistry approach makes it possible for the first time to distinguish among HCO 3- , CO 3= , and H + fluxes, thereby providing insight into molecular actions of clinically relevant acid-base transporters and carbonic-anhydrase inhibitors.
Alper,
Molecular physiology and genetics of Na+-independent SLC4 anion exchangers.
2009, Pubmed
Alper,
Molecular physiology and genetics of Na+-independent SLC4 anion exchangers.
2009,
Pubmed
Arakawa,
Crystal structure of the anion exchanger domain of human erythrocyte band 3.
2015,
Pubmed
Bae,
Chaperone stress 70 protein (STCH) binds and regulates two acid/base transporters NBCe1-B and NHE1.
2013,
Pubmed
,
Xenbase
Barbuskaite,
NBCe2 (Slc4a5) Is Expressed in the Renal Connecting Tubules and Cortical Collecting Ducts and Mediates Base Extrusion.
2020,
Pubmed
Becker,
Carbonic anhydrase II increases the activity of the human electrogenic Na+/HCO3- cotransporter.
2007,
Pubmed
,
Xenbase
Boedtkjer,
Disruption of Na+,HCO₃⁻ cotransporter NBCn1 (slc4a7) inhibits NO-mediated vasorelaxation, smooth muscle Ca²⁺ sensitivity, and hypertension development in mice.
2011,
Pubmed
Boedtkjer,
Na+,HCO3- cotransporter NBCn1 accelerates breast carcinogenesis.
2019,
Pubmed
Boron,
Intracellular pH transients in squid giant axons caused by CO2, NH3, and metabolic inhibitors.
1976,
Pubmed
Boron,
Intracellular pH-regulating mechanism of the squid axon. Interaction between DNDS and extracellular Na+ and HCO3-.
1989,
Pubmed
Boron,
Na(+)-dependent Cl-HCO3 exchange in the squid axon. Dependence on extracellular pH.
1992,
Pubmed
Boron,
Stoichiometry and ion dependencies of the intracellular-pH-regulating mechanism in squid giant axons.
1983,
Pubmed
Boron,
Intracellular pH-regulating mechanism of the squid axon. Relation between the external Na+ and HCO-3 dependences.
1985,
Pubmed
Boron,
Evaluating the role of carbonic anhydrases in the transport of HCO3--related species.
2010,
Pubmed
Boton,
Two calcium-activated chloride conductances in Xenopus laevis oocytes permeabilized with the ionophore A23187.
1989,
Pubmed
,
Xenbase
Calvetti,
Computational model of electrode-induced microenvironmental effects on pH measurements near a cell membrane.
2020,
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
Christensen,
The choroid plexus sodium-bicarbonate cotransporter NBCe2 regulates mouse cerebrospinal fluid pH.
2018,
Pubmed
Dodgson,
Topiramate as an inhibitor of carbonic anhydrase isoenzymes.
2000,
Pubmed
Grichtchenko,
Depolarization-induced acid secretion in gliotic hippocampal slices.
1994,
Pubmed
Grichtchenko,
Cloning, characterization, and chromosomal mapping of a human electroneutral Na(+)-driven Cl-HCO3 exchanger.
2001,
Pubmed
,
Xenbase
Guo,
Na+/HCO3- Cotransporter NBCn2 Mediates HCO3- Reclamation in the Apical Membrane of Renal Proximal Tubules.
2017,
Pubmed
Gurnett,
Disruption of sodium bicarbonate transporter SLC4A10 in a patient with complex partial epilepsy and mental retardation.
2008,
Pubmed
Hartley,
DNA cloning using in vitro site-specific recombination.
2000,
Pubmed
Huynh,
CryoEM structure of the human SLC4A4 sodium-coupled acid-base transporter NBCe1.
2018,
Pubmed
Jentsch,
Kinetic properties of the sodium bicarbonate (carbonate) symport in monkey kidney epithelial cells (BSC-1). Interactions between Na+, HCO-3, and pH.
1986,
Pubmed
Kao,
Human SLC4A11-C functions as a DIDS-stimulatable H⁺(OH⁻) permeation pathway: partial correction of R109H mutant transport.
2015,
Pubmed
Lee,
Exploring the autoinhibitory domain of the electrogenic Na+ /HCO3- transporter NBCe1-B, from residues 28 to 62.
2018,
Pubmed
,
Xenbase
Lee,
Substrate specificity of the electrogenic sodium/bicarbonate cotransporter NBCe1-A (SLC4A4, variant A) from humans and rabbits.
2013,
Pubmed
,
Xenbase
Lee,
Monitoring ion activities in and around cells using ion-selective liquid-membrane microelectrodes.
2013,
Pubmed
Lee,
Relief of autoinhibition of the electrogenic Na-HCO(3) [corrected] cotransporter NBCe1-B: role of IRBIT vs.amino-terminal truncation.
2012,
Pubmed
,
Xenbase
Liman,
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs.
1992,
Pubmed
,
Xenbase
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
Moss,
Carbonic anhydrases enhance activity of endogenous Na-H exchangers and not the electrogenic Na/HCO3 cotransporter NBCe1-A, expressed in Xenopus oocytes.
2020,
Pubmed
,
Xenbase
Musa-Aziz,
Evidence from simultaneous intracellular- and surface-pH transients that carbonic anhydrase IV enhances CO2 fluxes across Xenopus oocyte plasma membranes.
2014,
Pubmed
,
Xenbase
Musa-Aziz,
Relative CO2/NH3 selectivities of AQP1, AQP4, AQP5, AmtB, and RhAG.
2009,
Pubmed
,
Xenbase
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
Musa-Aziz,
Evidence from simultaneous intracellular- and surface-pH transients that carbonic anhydrase II enhances CO2 fluxes across Xenopus oocyte plasma membranes.
2014,
Pubmed
,
Xenbase
Myers,
Mouse Slc4a11 expressed in Xenopus oocytes is an ideally selective H+/OH- conductance pathway that is stimulated by rises in intracellular and extracellular pH.
2016,
Pubmed
,
Xenbase
Niculescu,
Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach.
2015,
Pubmed
Occhipinti,
Evidence from mathematical modeling that carbonic anhydrase II and IV enhance CO2 fluxes across Xenopus oocyte plasma membranes.
2014,
Pubmed
,
Xenbase
Okuyama,
Genomic organization and localization of gene for human carbonic anhydrase IV to chromosome 17q.
1993,
Pubmed
Parker,
Characterization of human SLC4A10 as an electroneutral Na/HCO3 cotransporter (NBCn2) with Cl- self-exchange activity.
2008,
Pubmed
,
Xenbase
Parker,
The divergence, actions, roles, and relatives of sodium-coupled bicarbonate transporters.
2013,
Pubmed
Parker,
Cloning and characterization of novel human SLC4A8 gene products encoding Na+-driven Cl-/HCO3(-) exchanger variants NDCBE-A, -C, and -D.
2008,
Pubmed
,
Xenbase
Piermarini,
Evidence against a direct interaction between intracellular carbonic anhydrase II and pure C-terminal domains of SLC4 bicarbonate transporters.
2007,
Pubmed
Pushkin,
Cloning, characterization and chromosomal assignment of NBC4, a new member of the sodium bicarbonate cotransporter family.
2000,
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
Ramsey,
A voltage-gated proton-selective channel lacking the pore domain.
2006,
Pubmed
Reithmeier,
A membrane metabolon linking carbonic anhydrase with chloride/bicarbonate anion exchangers.
2001,
Pubmed
Romero,
The SLC4 family of bicarbonate (HCO₃⁻) transporters.
2013,
Pubmed
Romero,
Expression cloning and characterization of a renal electrogenic Na+/HCO3- cotransporter.
1997,
Pubmed
,
Xenbase
Roos,
Intracellular pH.
1981,
Pubmed
Sasaki,
A voltage sensor-domain protein is a voltage-gated proton channel.
2006,
Pubmed
Shirakabe,
IRBIT, an inositol 1,4,5-trisphosphate receptor-binding protein, specifically binds to and activates pancreas-type Na+/HCO3- cotransporter 1 (pNBC1).
2006,
Pubmed
,
Xenbase
Soleimani,
Ionic mechanism of Na+-HCO3- cotransport in rabbit renal basolateral membrane vesicles.
1989,
Pubmed
Somersalo,
A reaction-diffusion model of CO2 influx into an oocyte.
2012,
Pubmed
,
Xenbase
Sowah,
An intramolecular transport metabolon: fusion of carbonic anhydrase II to the COOH terminus of the Cl(-)/HCO(3)(-)exchanger, AE1.
2011,
Pubmed
Sterling,
The extracellular component of a transport metabolon. Extracellular loop 4 of the human AE1 Cl-/HCO3- exchanger binds carbonic anhydrase IV.
2002,
Pubmed
Sterling,
A transport metabolon. Functional interaction of carbonic anhydrase II and chloride/bicarbonate exchangers.
2001,
Pubmed
Stewart,
Interactions of mouse glycophorin A with the dRTA-related mutant G719D of the mouse Cl-/HCO3- exchanger Ae1.
2011,
Pubmed
,
Xenbase
Toye,
The human NBCe1-A mutant R881C, associated with proximal renal tubular acidosis, retains function but is mistargeted in polarized renal epithelia.
2006,
Pubmed
,
Xenbase
Vachel,
Modulation of Cl- signaling and ion transport by recruitment of kinases and phosphatases mediated by the regulatory protein IRBIT.
2018,
Pubmed
,
Xenbase
Vaughan-Jones,
Regulation of chloride in quiescent sheep-heart Purkinje fibres studied using intracellular chloride and pH-sensitive micro-electrodes.
1979,
Pubmed
Vorum,
Immunolocalization of electroneutral Na-HCO(3)(-) cotransporter in rat kidney.
2000,
Pubmed
Wang,
Effects of Nt-truncation and coexpression of isolated Nt domains on the membrane trafficking of electroneutral Na+/HCO3- cotransporters.
2015,
Pubmed
,
Xenbase
Wang,
Cryo-EM structure of the sodium-driven chloride/bicarbonate exchanger NDCBE.
2021,
Pubmed
Wu,
Molecular insight into coordination sites for substrates and their coupling kinetics in Na+ /HCO3- cotransporter NBCe1.
2022,
Pubmed
,
Xenbase
Xu,
Slc4a8 in the Kidney: Expression, Subcellular Localization and Role in Salt Reabsorption.
2018,
Pubmed
Yang,
Down-regulated Solute Carrier Family 4 Member 4 Predicts Poor Progression in Colorectal Cancer.
2020,
Pubmed
Zhu,
Missense mutation T485S alters NBCe1-A electrogenicity causing proximal renal tubular acidosis.
2013,
Pubmed
