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

Abstract

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 SO₄^2–/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.