2.A.31 The Anion Exchanger (AE) Family

Characterized protein members of the AE family are found in animals, plants and yeast. Uncharacterized AE homologues are present in bacteria (e.g., in Entercoccus faecium, 372 aas; gi 22992757; 29% identity in 90 residues). The animal AE proteins consist of homodimeric complexes of integral membrane proteins that vary in size from about 900 amino acyl residues to about 1250 residues. Their N-terminal hydrophilic domains may interact with cytoskeletal proteins and therefore play a cell structural role. The human AE1 binds carbonic anhydrase II (CAII) forming a "transport metabolon" as CAII binding activates AE1 transport activity about 10 fold (Sterling et al., 2001). AE1 is also activated by interaction with glycophorin which also functions to target it to the plasma membrane (Young and Tanner, 2003). The membrane-embedded C-terminal domains may each span the membrane 13-16 times. According to the model of Zhu et al. (2003), it spans the membrane 16 times, 13 times as α-helix, and three times (TMSs 10, 11 and 14) possibly as β-strands. They preferentially catalyze anion exchange (antiport) reactions. There are three known paralogous isoforms of anion exhangers (AE1, AE2 and AE3) in mammals such as mice and rats. The different isoforms have different tissue distributions.

AE1 in human red blood cells has been shown to transport a variety of inorganic and organic anions. Divalent anions may be symported with H⁺. Additionally, it catalyzes flipping of several anionic amphipathic molecules such as sodium dodecyl sulfate (SDS) and phosphatidic acid from one monolayer of the phospholipid bilayer to the other monolayer. The rate of flipping is sufficiently rapid to suggest that this AE1-catalyzed process is physiologically important in red blood cells and possibly in other animal tissues as well. Anionic phospholipids and fatty acids are likely to be natural substrates.

Renal Na⁺:HCO₃^- cotransporters have been found to be members of the AE family. They catalyze the reabsorption of HCO₃^- in the renal proximal tubule in an electogenic process that is inhibited by typical stilbene inhibitors of AE such as DIDS and SITS. They are also found in many other body tissues. At least two genes encode these symporters in any one mammal. A 10 TMS model has been presented (Romero and Boron, 1999), but this model conflicts with the 14 TMS model proposed for AE1. The transmembrane topology of the human pancreatic electrogenic Na⁺:HO₃^- transporter, NBC1, has been studied (Tatishchev et al., 2003). A TMS topology with N- and C-termini in the cytoplasm has been suggested.

In addition to the Na⁺-independent anion exchangers (AE1-3) and the Na⁺:HCO₃^- cotransporters (NBCs) (which may be either electroneutral or electrogenic), a Na⁺-driven HCO₃^-/Cl^- exchanger (NCBE) has been sequenced and characterized (Wang et al., 2000). It transports Na⁺ + HCO₃^- preferentially in the inward direction and H⁺ + Cl^- in the outward direction. This NCBE is widespread in mammalian tissues where it plays an important role in cytoplasmic alkalinization. For example, in pancreatic β-cells, it mediates a glucose-dependent rise in pH related to insulin secrection.

K⁺:HCO₃^- cotransport has also been reported to occur in mammalian cells, but the carrier responsible for this activity has not yet been cloned or identified.

Animal cells in tissue culture expressing the gene-encoding the ABC-type chloride channel protein CFTR (TC #3.A.1.202.1) in the plasma membrane have been reported to exhibit cyclic AMP-dependent stimulation of AE activity. Regulation was independent of the Cl^- conductance function of CFTR, and mutations in the nucleotide-binding domain #2 of CFTR altered regulation independently of their effects on chloride channel activity. These observations may explain impaired HCO₃^- secretion in cystic fibrosis patients.

Plants and yeast have anion transporters that in both the pericycle cells of plants and the plasma membrane of yeast cells export borate or boric acid (pKa = 9.2) (referred to below as "boron") (Takano et al., 2002). In A. thaliana, boron is exported from pericycle cells into the root stelar apoplasm against a concentration gradient for uptake into the shoots. In S. cerevisiae, export is also against a concentration gradient. The yeast transporter recognizes HCO₃^-, I^-, Br^-, NO₃^- and Cl^- which may be substrates. The mechanism of energy coupling is not known, nor is it known if borate or boric acid is the substrate. Several possibilities (uniport, anion:anion exchange and anion:cation exchange) can account for the data (Takano et al., 2002).

The physiologically relevant transport reaction catalyzed by anion exchangers of the AE family is:

Cl^- (in) + HCO₃^- (out) Cl^- (out) + HCO₃^- (in).

That for the Na⁺:HCO₃^- cotransporters is:

Na⁺ (out) + nHCO₃^- (out) → Na⁺ (in) + nHCO₃^- (in).

That for the Na⁺/HCO₃^-:H⁺/Cl^- exchanger is:

Na⁺ (out) + HCO₃^- (out) + H⁺ (in) + Cl^- (in) Na⁺ (in) + HCO₃^- (in) + H⁺ (out) + Cl^- (out).

That for the boron efflux protein of plants and yeast is:

boron (in) → boron (out)

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