The SLC4 Anion Exchanger Gene Family

Transmembrane transport of HCO − 3 and CO 2 is central to body pH and volume homeostasis. The Na + -independent, electroneutral CI − /HCO − 3 exchangers AE1/Band 3 and the related AE2 and AE3 polypeptides of the SLC4 gene family play central roles in these processes. The SLC4/AE anion exchangers regulate intracellular pH and, through their polarized localization in renal and other epithelial cells, regulate compartmental and systemic pH. SLC4/AE anion exchangers also regulate cell volume and modulate the cellular equilibrium potential for Cl − , thus contributing to determination of driving forces for multiple ion transport pathways throughout the body. Distinct mutations of human AE1 cause distal renal tubular acidosis, spherocytic hemolytic anemia, and cation-leak stomatocytosis. Lack of AE2 in the mouse causes early death with osteopetrosis and wide impairment of epithelial secretion. Lack of AE3 in the mouse causes late-onset retinal degeneration and increases susceptibility to seizures and heart failure. These phenotypes illustrate the consequences of disrupting local and/or systemic bicarbonate/chloride homeostasis.