Molecular physiology and genetics of Na+-independent SLC4 anion exchangers.
Plasmalemmal Cl(-)/HCO(3)(-) exchangers are encoded by the SLC4 and SLC26 gene superfamilies, and function to regulate intracellular pH, [Cl(-)] and cell volume. The Cl(-)/HCO(3)(-) 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(-)/HCO(3)(-) 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 SO(4)(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.
Alper
Seth L
SL
Renal Division and Molecular and Vascular Medicine Unit, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. salper@bidmc.harvard.edu
D000818:Animals; D002462:Cell Membrane; D006801:Humans; D051379:Mice; D011487:Protein Conformation; D012964:Sodium / Q000378:metabolism*; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D027982:Sodium-Bicarbonate Symporters; D012964:Sodium