Molecular physiology and genetics of Na+-independent SLC4 anion exchangers

Plasmalemmal Cl-/HCO3- exchangers are encoded by the SLC4 and SLC26 gene superfamilies, and function to regulate intracellular pH, [Cl-] and cell volume. The Cl-/HCO3- exchangers of polarized epithelial cells also contribute to transepithelial secretion and reabsorption of acid-base equivalents and Cl-. This review focuses on Na+- independent electroneutral Cl-/HCO3 exchangers of the SLC4 family. Human SLC4A1/AE1 mutations cause the familial erythroid disorders of spherocytic anemia, stomatocytic anemia and ovalocytosis. A largely discrete set of AE1 mutations causes familial distal renal tubular acidosis. The Slc4a2/Ae2(-/-) mouse dies before weaning with achlorhydria and osteopetrosis. A hypomorphic Ae2(-/-) mouse survives to exhibit male infertility with defective spermatogenesis and a syndrome resembling primary biliary cirrhosis. A human SLC4A3/AE3 polymorphism is associated with seizure disorder, and the Ae3(-/-) mouse has increased seizure susceptibility. The transport mechanism of mammalian SLC4/AE polypeptides is that of electroneutral Cl-/anion exchange, but trout erythroid Ae1 also mediates Cl- conductance. Erythroid Ae1 may mediate the DIDS-sensitive Cl- conductance of mammalian erythrocytes, and, with a single missense mutation, can mediate electrogenic SO42-/Cl- exchange. AE1 trafficking in polarized cells is regulated by phosphorylation and by interaction with other proteins. AE2 exhibits isoform-specific patterns of acute inhibition by acidic intracellular pH and independently by acidic extracellular pH. In contrast, AE2 is activated by hypertonicity and, in a pH-independent manner, by ammonium and by hypertonicity. A growing body of structure-function and interaction data, together with emerging information about physiological function and structure, is advancing our understanding of SLC4 anion exchangers.