title: Molecular physiology of SLC4 anion exchangers.
abstract: Plasmalemmal Cl- -HCO3- exchangers regulate intracellular pH and [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 haemolytic anaemia 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 modelled to form contiguous surface patches on the AE2 cytoplasmic domain. In contrast, the N-terminal variant AE2c polypeptide exhibits an alkaline-shifted pHo 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.
authors.affiliation: Molecular and Vascular Medicine Unit, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. salper@bidmc.harvard.edu
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
mesh_terms: D000141:Acidosis, Renal Tubular / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D027321:Anion Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017920:Antiporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002256:Carbonic Anhydrases / Q000378:metabolism; D027963:Chloride-Bicarbonate Antiporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004612:Elliptocytosis, Hereditary / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D005810:Multigene Family; D009154:Mutation; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D064606:SLC4A Proteins; D013103:Spherocytosis, Hereditary / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; D027321:Anion Transport Proteins; D017920:Antiporters; D027963:Chloride-Bicarbonate Antiporters; D064606:SLC4A Proteins; C454201:SLC4A1 protein, human; C579496:SLC4A2 protein, human; C489237:SLC4A3 protein, human; C579495:Slc4a2 protein, mouse; D002256:Carbonic Anhydrases