SUMMARY: 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.

Autosomal dominant polycystic kidney disease (ADPKD) gene products polycystin-1 (PC1) and polycystin-2 (PC2) colocalize in the apical monocilia of renal epithelial cells. Mouse and human renal cells without PC1 protein show impaired ciliary mechanosensation, and this impairment has been proposed to promote cystogenesis. However, most cyst epithelia of human ADPKD kidneys appear to express full-length PC1 and PC2 in normal or increased abundance. We show that confluent primary ADPKD cyst cells with the novel PC1 mutation ΔL2433 and with normal abundance of PC1 and PC2 polypeptides lack ciliary PC1 and often lack ciliary PC2, whereas PC1 and PC2 are both present in cilia of confluent normal human kidney (NK) epithelial cells in primary culture. Confluent NK cells respond to shear stress with transient increases in cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i), dependent on both extracellular Ca²⁺ and release from intracellular stores. In contrast, ADPKD cyst cells lack flow-sensitive [Ca²⁺]_i signaling and exhibit reduced endoplasmic reticulum Ca²⁺ stores and store-depletion-operated Ca²⁺ entry but retain near-normal [Ca²⁺]_i responses to ANG II and to vasopressin. Expression of wild-type and mutant CD16.7-PKD1(115–226) fusion proteins reveals within the COOH-terminal 112 amino acids of PC1 a coiled-coil domain-independent ciliary localization signal. However, the coiled-coil domain is required for CD16.7-PKD1(115–226) expression to accelerate decay of the flow-induced Ca²⁺ signal in NK cells. These data provide evidence for ciliary dysfunction and polycystin mislocalization in human ADPKD cells with normal levels of PC1.

Mutations in the human SLC26A3 gene, also known as down‐regulated in adenoma (hDRA), cause autosomal recessive congenital chloride‐losing diarrhoea (CLD). hDRA expressed in Xenopus oocytes mediated bidirectional Cl⁻‐Cl⁻ and Cl⁻‐HCO₃⁻ exchange. In contrast, transport of oxalate was low, and transport of sulfate and of butyrate was undetectable. Two CLD missense disease mutants of hDRA were nonfunctional in oocytes. Truncation of up to 44 C‐terminal amino acids from the putatively cytoplasmic C‐terminal hydrophilic domain left transport function unimpaired, but deletion of the adjacent STAS (sulfate transporter anti‐sigma factor antagonist) domain abolished function. hDRA‐mediated Cl⁻ transport was insensitive to changing extracellular pH, but was inhibited by intracellular acidification and activated by NH₄⁺ at acidifying concentrations. These regulatory responses did not require the presence of either hDRA's N‐terminal cytoplasmic tail or its 44 C‐terminal amino acids, but they did require more proximate residues of the C‐terminal cytoplasmic domain. Although only weakly sensitive to inhibition by stilbenes, hDRA was inhibited with two orders of magnitude greater potency by the anti‐inflammatory drugs niflumate and tenidap. cAMP‐insensitive Cl⁻‐HCO₃⁻ exchange mediated by hDRA gained modest cAMP sensitivity when co‐expressed with cystic fibrosis transmembrane conductance regulator (CFTR). Despite the absence of hDRA transcripts in human cell lines derived from CFTR patients, DRA mRNA was present at wild‐type levels in proximal colon and nearly so in the distal ileum of CFTR(‐/‐) mice. Thus, pharmacological modulation of DRA might be a useful adjunct treatment of cystic fibrosis.