Anion exchanger (AE, AE1, 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 (TC# 8.A.168.1.1; 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), 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. CryoEM structures of AE1 capture multiple states of inward- and outward-facing conformations (Zhekova et al. 2022). AE1 is the primary bicarbonate transporter in erythrocytes, regulating pH levels and CO₂ transport between lungs and tissues. Capper et al. 2023 revealed molecular features of substrate recognition and transport and illuminated sterol binding sites, to elucidate distinct inhibitory mechanisms of research chemicals and prescription drugs. They further probed the substrate binding site via structure-based ligand screening, identifying an AE1 inhibitor.  Impaired trafficking and instability of mutant kidney anion exchanger 1 proteins are associated with autosomal recessive distal renal tubular acidosis (Deejai et al. 2022). Capper et al. 2023 presented seven cryo-EM structures in apo, bicarbonate-bound and inhibitor-bound states. These revealed molecular features of substrate recognition and transport, and illuminate sterol binding sites, to elucidate distinct inhibitory mechanisms of research chemicals and prescription drugs (Capper et al. 2023). A variant of SLC4A1 causes hereditary spherocytosis (Li et al. 2022).  Mutations in SLC4A1),encoding anion exchanger 1 (AE1) are a common cause of autosomal recessive distal renal tubular acidosis (AR dRTA) (Deejai et al. 2022). Cryo-EM structures of the human band 3 transporter indicate a transport mechanism involving the coupled movement of chloride and bicarbonate ions in an elevator-type process (Su et al. 2024). Residue R730 of Band 3 is the most probable binding site for bicarbonate ions. Cholesterol enhances bicarbonate ion binding by influencing the conformational stability of Band 3 and compressing the volume of the Band 3 cavity (Lv et al. 2024).