Received October 5, 2005
Revised October 6, 2005
Accepted after revision October 13, 2005

¹ Beth Israel Deaconess Med. Ctr. and Harvard Medical School

^* To whom correspondence should be addressed. E-mail: salper{at}bidmc.harvard.edu.

	Abstract

Plasmalemmal Cl^-/HCO₃^- exchangers regulate intracellular pH, [Cl^-], and cell volume. In polarized epithelial cells they contribute also to transepithelial secretion and reabsorption of acid-base equivalents and of Cl^-. Members of both the SLC4 and SLC26 mammalian gene families encode Na+-independent Cl^-/HCO₃^- exchangers. Human SLC4A1/AE1 mutations cause either the erythroid disorders spherocytic hemolytic anemia or ovalocytosis, or distal renal tubular acidosis. SLC4A2/AE2 knockout mice die at weaning. Human SLC4A3/AE3 polymorphisms have been associated with seizure disorder. Although mammalian SLC4/AE polypeptides mediate only electroneutral Cl^-/anion exchange, trout erythroid AE1 also promotes osmolyte transport and increased anion conductance. Mouse AE1 is required for DIDS-sensitive erythroid Cl^- conductance, but definitive evidence for mediation of Cl^- conductance is lacking. However, a single missense mutation allows AE1 to mediate both electrogenic SO₄^2-/Cl^- exchange or electroneutral, H⁺-independent SO₄^2-/ SO₄^2- exchange. In the Xenopus oocyte, the AE1 C-terminal cytoplasmic tail residues reported to bind carbonic anhydrase II are dispensable for Cl^-/Cl^- exchange, but required for Cl^-/HCO₃^-exchange. AE2 is acutely and independently inhibited by intracellular and extracellular H⁺, and this regulation requires integrity of the most highly conserved sequence of the AE2 N-terminal cytoplasmic domain. Individual missense mutations within this and adjacent regions identify additional residues which acid-shift pHo sensitivity. These regions together are modeled to form contiguous surface patches on the AE2 cytoplasmic domain. In contrast, the N-terminal variant AE2c polypeptide exhibits an alkaline-shifted pH_o-sensitivity, as do certain transmembrane domain His mutants. AE2-mediated anion exchange is also stimulated by ammonium and by hypertonicity by a mechanism sensitive to inhibition by chelation of intracellular Ca²⁺ and by calmidazolium. This growing body of structure-function data, together with increased structural information, will advance mechanistic understanding of SLC4 anion exchangers.

Key Words: Bicarbonate, Chloride transport, Transport regulation