Anion exchanger (AE, HCO₃^-:Cl^- antiporter; also called Band 3 or CDB3; SLC4a1, Q9BWU0) transports a variety of inorganic and organic anions. Anionic phospholipids are ''flipped'' from one monolayer to the other in erythrocytes and the nephron. Mutations cause Southeast Asian ovalocytosis (SAO) hereditary spherocytosis and distal renal tubular acidosis (dRTA) with impaired acid secretion in humans (Chu et al., 2010; Kittanakom et al., 2008; Toye et al., 2008). It is activated by glycophorin A (Stewart et al., 2011). Glycophorin has been reported to interact with kidney AE1 (Chen et al. 1998), but Kittanakom et al. 2005 could not detect this interaction. Hübner et al. 2002, 2003 reported nuclear and mitochondrial targetting of kanadaptin.  Some point mutations in AE allow the normally electroneutral anion exchanger to catalyze Na⁺ and K⁺ conductance or induce a cation leak in the still functional anion exchanger. A structural model of the AE1 membrane spanning domain, based on the structure of the uracil-proton symporter, suggests that there is a unique transport site comprising TMSs 3-5 and 8 that may function in anion exchange and cation leak (Barneaud-Rocca et al. 2013). The spectrin-actin-based cytoskeletal network is attached to the plasma membrane through interactions with ankyrin, which binds to both spectrin and a beta-hairpin loop in the cytoplasmic domain of band 3 (Stefanovic et al. 2007). A detailed transport mechanism has been proposed. It involves an elevator-like motion of the substrate-binding domain relative to the nearly stationary dimerization domain and to the membrane plane (Ficici et al. 2017). The structure-function relationships of band 3 have been reviewed (Abbas et al. 2018). Interaction of the human erythrocyte Band 3 with lipids and glycophorin A have revealed the molecular organization of the Wright (Wr) blood group antigen (Kalli and Reithmeier 2018). Some inhibitors of carbonic anhydrase in the 0.22-2.8 microM range also inhibit anion exchage catalyzed by AE1 (Morgan et al. 2015). The molecular mechanisms and physiological roles of HCO3^- permeation through anion channels has been reviewed (Shin et al. 2020). Nifedipine is both an activator (fast) and de-activator (slow) of CDB3 (Yastrebova et al. 2019). The substrate anion selectivity filter may be in the V849 to L863 region of the protein (Zhu and Casey 2004). R730 in hAE1 is crucial for anion binding to both the entry and central sites, while in hNBCe1 (TC# 2.A.31.2.12), a Na⁺ acts as an anchor for CO₃^2- binding to the central site. Protonation of the central acidic residues (E681 in hAE1 and D754 in hNBCe1) alters the ion dynamics in the permeation cavity and may contribute to the transport mode differences in SLC4 proteins (Zhekova et al. 2021). The past 150 years of research on AE have been reviewed (Jennings 2021). A missense mutation in AE1 causes autosomal dominant distal renal tubular acidosis although the transporter retains normal transport function (Rungroj et al. 2004). It is mistargeted in polarized epithelial cells. Band3-mediated anion transport is reduced upon HgCl₂ treatment (Notariale et al. 2022). AE1 (Slc4A1) transports CO3^-- (Lee et al. 2022). AE1 is the main erythroid Cl^-/HCO₃^- transporter that supports CO₂ transport. Glycophorin A (GPA), a component of the AE1 complexes, facilitates AE1 expression and anion transport, but Glycophorin B (GPB) does not (Hsu et al. 2022). There are forward-trafficking and transmembrane-driven ER/Golgi retention signals encoded in glycophorin sequences.

Animals

SLC4A1 of Homo sapiens

Anion exchanger-2 (AE2; 1241 aas); catalyzes solium-independent Cl^-:HCO₃^- exchange; forms a metabolon with the carbonic anhydrase, Car2 (AAH11949) (Gonzalez-Begne et al., 2007) and with another carbonic anhydrase, CAIX (Q16790) which also forms complexes with AE1 and AE3, activating all of these  transporters about 30% (Morgan et al. 2007).  Cys residues play a role in pH sensitivity, but are not essential for activity (Reimold et al. 2013).

Animals

SLC4A2 of Homo sapiens

Anion exchange protein 3 (AE 3; AE3) (Anion exchanger 3) (CAE3/BAE3) (Cardiac/brain band 3-like protein) (Neuronal band 3-like protein) (Solute carrier family 4 member 3).  The motif LDADD is a binding site for the N-terminal basic region of carbonic ahnydride II (not I), facilitating bicarbonate transport (Moraes and Reithmeier 2012). An isoform of this Na⁺-independent Cl^-/HCO₃^- exchanger is involved in myocardial pH_i recovery from intracellular alkalization (Chiappe de Cingolani et al. 2006).

Animals

SLC4A3 of Homo sapiens

Anion exchanger 1 (AE1, Band 3 anion exchanger, Slc4a1) of 918 aas and 13 TMSs in a 1 + 12 TMS arrangement that looks like a 1 + 6 + 6 arrangement.  The protein functions both as a transporter that mediates electroneutral inorganic anion exchange (e.g., Cl^- against HCO₃^-) across the cell membrane and as a structural protein. It is a major integral membrane glycoprotein of the erythrocyte membrane required for normal flexibility and stability of the erythrocyte membrane and for normal erythrocyte shape via the interactions of its N-terminal cytoplasmic domain with cytoskeletal proteins, glycolytic enzymes, and hemoglobin. It mediates chloride-bicarbonate exchange in the kidney, and is required for normal acidification of the urine. A mutant containing the sole C462 can drive a marginal Cl^- current, but the minimal configuration necessary to get optimal functional expression includes residues C462, C583 and C588 (Martial et al. 2007). Trout AE1 can function both as a antiporter or a channel, and mutations affecting one or the other function or both have been isolated (Martial et al. 2006).

AE1 of Oncorhynchus mykiss (Rainbow trout) (Salmo gairdneri)

The Na⁺-driven Cl^--HCO₃^- exchanger, ABTS-1 (extrudes Cl^- from the cell) (Bellemer et al., 2011).

Animals

ABTS-1 of Caenorhabditis elegans (B3WFV9)

Sodium bicarbonate cotransporter 3, NBCn1, (also referred to as sodium bicarbonate cotransporter 2) (sodium bicarbonate cotransporter 2b) (bicarbonate transporter) (Solute carrier family 4 member 7) of 1214 aas and 12 TMSs in an apparent 4 + 8 TMS arrangement. Acid-base homeostasis is critical for proper physiological function and pathology. The SLC4 family of HCO₃^-  cotransporters are amoung the HCO₃^- carriers responsible for cellular pH regulation and the uptake or secretion of HCO₃^- in epithelial cells. NBCn1 is an electroneutral Na⁺/HCO₃^- cotransporter, expressed in several tissues that functions in acid extrusion after cellular acidification. It is also involved in other processes such as cell volume, cell death/survival balance, transepithelial transport, and regulation of cell viability. Wang et al. 2022 have reviewed recent advances in the research of NBCn1, emphasizing basic features, regulation, and tissue-specific physiology as well as the use of potent inhibitors of NBCn1 transporter in cancer therapy.

Animals

SLC4A7 of Homo sapiens

Electrogenic sodium bicarbonate cotransporter 1, NBCe1 (Sodium bicarbonate cotransporter, NBC) (Na⁺/HCO3^- cotransporter) (Solute carrier family 4 member 4) (kNBC1) of 1079 aas (Boron et al. 2009). Mutations cause proximal renal tubular acidosis and ocular pathology (Demirci et al. 2006). NBCe1, together with carbonic anhydrase II, CAII, provides an efficient mechanism of bicarbonate sensing in cortical astrocytes (Theparambil et al. 2017). NBCe1-B is widely expressed in many tissues, including the pancreas, submandibular gland, brain, heart, etc. It has very low activity under basal conditions due to auto-inhibition, but can be fully activated by interaction with IRBIT (TC# 8.A.151.1.1). IRBIT activates NBCe1-B by releasing the auto-inhibition module from the transmembrane domain (Su et al. 2020). NHE-3 (TC# 2.A.53.2.18) was markedly downregulated, while NBCe1 and the Na⁺-glucose transporter type-2 (SGLT2 or SGLT-2; TC#2.A.1.7.26) were upregulated after kidney transplantation (Velic et al. 2004). NBCe1 transports CO₂ (Michenkova et al. 2021). R730 in hAE1 (TC# 2.A.31.1.1) is crucial for anion binding to both the entry and central sites, while in hNBCe1, a Na⁺ acts as an anchor for CO₃^2- binding to the central site. Protonation of central acidic residues (E681 in hAE1 and D754 in hNBCe1) alters the ion dynamics in the permeation cavity and may contribute to the transport mode differences in SLC4 proteins (Zhekova et al. 2021). The phosphorylation status of Ser982 is not a key determinant of NBCe1 stoichiometry but correlates with NBCe1 activity (Alsufayan et al. 2021). NBCe1 in the influx mode may move 1 Na⁺ + 2 HCO₃^- across the plasma membrane, whereas in the efflux mode, it moves 1 Na⁺ +1 HCO₃^- +1 CO₃^2- (Wu et al. 2022). However, Lee et al. 2022 concluded that CO₂^{2- is the transported species.}

Animals

SLC4A4 of Homo sapiens

Sodium-driven chloride bicarbonate exchanger (Solute carrier family 4 member 10) of 1118 aas and 12 or 14 TMSs.  This protein and SLC4A1 (TC# 2.A.31.1.1) are down-regulated in Meniere's disease (Sun et al. 2018).

Animals

SLC4A10 of Homo sapiens

Sodium bicarbonate cotransporter, NBC, of 1194 aas and 12 TMSs. It can transport HCO₃^- (or a related species, such as CO₃^2-).  It functions in adaptation to pH stress, both acid- and base-stress (Cai et al. 2017).

NBC of Litopenaeus vannamei (Pacific white shrimp)

Probable electroneutral Na⁺-driven bicarbonate transporter, NBC, of 1214 aas and 13 putative TMSs. It possibly functions by Cl^- exchange as does the human ortholog (TC# 2.A.31.2.4). It is present in the flagellar plasma membrane (Gunaratne et al. 2006).

NBC of Strongylocentrotus purpuratus

Electrogenic sodium bicarbonate cotransporter 4, NBC4 or SLC4A5, of 1137 aas and probably 12 TMSs in a 4 + 4 + 2 + 2 TMS arrangement (Sassani et al. 2002). NBC1 and NBC4 are electrogenic due to the coupling of one anionic and two cationic fluxes during each transport cycle. Other sodium bicarbonate cotransporters and members of the bicarbonate transporter superfamily catalyze electroneutral processes (Kurtz et al. 2004). It may have a housekeeping function in regulating the pH of tissues in which it is expressed. It may also play a role in mediating Na⁺:HCO3^- cotransport in hepatocytes and intrahepatic cholangiocytes and could be important in protecting the renal paranchyma from alterations in the urinary pH.

NBC4 of Homo sapiens

Electrogenic Na⁺:HCO₃^- cotransporter, rkNBC (NBCI, NBCe1, SLC4A4). The human orthologue, NBCe1/SLC4A4;Q9Y6R1, is stimulated by carbonic anhydrase II and IX which together form a transport metabolon (Becker and Deitmer, 2007; Orlowski et al., 2012). The bicarbonate channel in the C-terminal two-thirds of the protein is regulated by the N-terminal hydrophilic domain (Chang et al., 2008) which may actually form part of the channel (Zhu et al. 2013). The topological location and structural importance of the NBCe1-A residues mutated in proximal renal tubular acidosis have been identified (Zhu et al., 2010). Defective membrane expression of the Na⁺/HCO₃^- cotransporter NBCe1 is associated with familial migraines (Suzuki et al., 2010). This transporter plays a role in pH regulation and bicarbonate transport in the kideny proximal tubule (Yamazaki et al., 2011; Zhu et al. 2013). The three lysyl residues in the KKMIK motif in TMS5 plays a role in DIDS inhibition (Lu and Boron 2007). Electrogenicity of NBCe1 probably depends on interactions between TM1-5 and TM6-13 (Choi et al. 2007). A I551F variant of NBCe1-A shows reduced cell surface expression, resulting in diminished transport activity (Yamazaki et al. 2021). Carbonic anhydrase IX is a marker of disease severity in obstructive sleep apnea (Geçkil et al. 2022).

Animals

rkNBC (NBCl) of Rattus norvegicus

Electrogenic Na⁺:HCO₃^- symporter/Cl^- antiporter, NCBE (regulates intracellular pH) (Wang et al., 2000; Damkier et al., 2010). Expressed in specific brain cell types; glycosylation required for functional expression (Chen et al., 2008). Loss reduces brain ventricle volume, impairs visual function and protects against fatal epileptic seizures in mice (Hilgen et al. 2012).  NCBE is involved in the control of neuronal pH and excitability; may contribute to the secretion of cerebrospinal fluid (Jacobs et al., 2008). The human orthologue (Q6U841) is an electroneutral Na⁺/HCO₃^- cotransporter (NBCn2 or NCBE) with Cl^- self exchange activity (Parker et al., 2008).  NCBE/NBCn2 is predominantly expressed in the central nervous system (CNS) with highest concentrations in the choroid plexus. Its primary function is to regulate intracellular neuronal pH and to maintain the pH homeostasis across the blood-cerebrospinal fluid barrier. NCBE is predicted to contain at least 10 transmembrane helices. The N- and C- termini are both cytoplasmic, with a large N-terminal domain (Nt-NCBE) and a relatively small C-terminal domain (Ct-NCBE). The Nt-NCBE is likely to be involved in bicarbonate recognition and transport and contains key areas of regulation involving pH sensing and protein-protein interactions.  It has an intrinsic disordered structure (Bjerregaard-Andersen et al. 2013).

Animals

NCBE of Mus musculus

Electroneutral Na⁺-driven HCO₃^-/Cl^- (+ H⁺) exchanger, NDCBE1; SLC4A8; NBCn1 (Boron et al. 2009). The crystal structure of the regulatory domain of the human sodium-driven chloride/bicarbonate exchanger  at 2.8 Å resolution has been determined (Alvadia et al. 2017).  It is essential for maintaining a homeostatic pH in neurons.  It forms an equivalent dimeric interface as observed for the cytoplasmic domain of Band 3, and thus establishes that the consensus motif VTVLP is the key minimal dimerization motif. It is highly conserved and likely to be the physiologically relevant interface for all other members of the AE family. A conserved Zn²⁺-binding motif present in the N-terminal domain of NDCBE was identified and characterized in vitro. Cellular studies confirmed the Zn²⁺-dependent transport of two electroneutral bicarbonate transporters, NCBE and NBCn1. The Zn²⁺ site was mapped to a cluster of histidines close to the conserved ETARWLKFEE motif and likely plays a role in the regulation of this motif (Alvadia et al. 2017). Lee et al. 2022 concluded that this system transporters Cl^- and HCO3^- in a Na⁺-dependent antiport process.

Animals

SLC4A8 of Homo sapiens

Squid Na⁺-dependent Cl^-/HCO₃^- symporter, NDCBE (1198 aas) (Piermarini et al., 2007b)

Squid

NDCBE of Loligo pealei (Q8I8G6)

Electrogenic HCO₃^-:Na⁺ symporter, NBCe2 (3:1 stoichiometry) (Millar and Brown, 2008)

Animals

SLC4A5 of Homo sapiens

The electrogenic Na⁺ bicarbonate cotransporter (NBCe1) (Sussman et al., 2009).

Animals

NBCe1 of Danio rerio (Q3ZMH2)

Boron efflux transporter for xylem loading (Takano et al., 2002; Miwa et al., 2010).  Fourteen borate transporters have been identified in wheat, and their expression patterns in terms of tissues, conditions and activities have been described (Wang et al. 2022).

Plants

BOR1 of Arabidopsis thaliana

Borate/boric acid (boron) efflux transporter, Bor1.  Involved in boron deficiency tolerance (Cañon et al. 2013).

Plants

Bor1 of Citrus macrophylla

Borate exporter of 666 aas and 13 TMSs with 5 cytooplasmic α-helices, Bot1.  Also known as the barley root anion-permeable transporter.  Confers tolerance to boron. It is believed to be trimeric.  Transport is dependent on Na⁺ (Nagarajan et al. 2016).

Bot1 of Hordeum vulgare

Inorganic anion transporter and exchanger, BOR1, of 701 aas and 11 TMSs.  It transports borate and other anions (Diehn et al. 2019).

BOR1 of Brassica napus (Rape)

Boron transporter, NcBC1 or SLC4a11. In the absence of borate, it functions as a Na⁺ and OH^- (H⁺) channel. In the presence of borate, it functions as an electrogenic Na⁺-coupled borate cotransporter (Park et al., 2004).  Three genetic corneal dystrophies (congenital hereditary endothelial dystrophy type 2 (CHED2), Harboyan syndrome and Fuchs endothelial corneal dystrophy (FECD) arise from mutations of the SLC4a11 gene, which cause blindness from fluid accumulation in the corneal stroma.  It can mediate water flux at a rate comparable to aquaporin in a process that is independent of solute transport (Vilas et al. 2013).  The systm has been reviewed by Patel and Parker 2015.  A 3-d homology model rationalizes various pathology-causing mutations (Badior et al. 2016). SLC4A11 is also a cell adhesion molecule involving extracellular loop 3, and cell adhesion defects contribute to FECD and CHED pathology (Malhotra et al. 2019). pH-dependence of Slc4a11-mediated H⁺ conductance is influenced by intracellular lysine residues and modified by disease-linked mutations (Quade et al. 2020). Corneal dystrophy mutations R125H and R804H disable SLC4A11 by altering the extracellular pH dependence of the intracellular pK that governs H⁺/OH^- transport  (Quade et al. 2022).

Animals

SLC4A11 of Homo sapiens