Affiliation:
1. Renal Division and Molecular and Vascular Medicine Unit, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Abstract
SUMMARYPlasmalemmal 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.
Publisher
The Company of Biologists
Subject
Insect Science,Molecular Biology,Animal Science and Zoology,Aquatic Science,Physiology,Ecology, Evolution, Behavior and Systematics
Cited by
186 articles.
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