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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Mouse Ae1 E699Q mediates SO₄^2–_i/anion_o exchange with [SO₄^2–]_i-dependent reversal of wild-type pH_o sensitivity

¹Molecular and Vascular Medicine Unit and the Renal Division, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts; ²Department of Psychology, Wellesley College, Wellesley, Massachusetts; and ³Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Submitted 20 February 2008 ; accepted in final form 7 May 2008

The SLC4A1/AE1 gene encodes the electroneutral Cl^–/HCO₃^– exchanger of erythrocytes and renal type A intercalated cells. AE1 mutations cause familial spherocytic and stomatocytic anemias, ovalocytosis, and distal renal tubular acidosis. The mutant mouse Ae1 polypeptide E699Q expressed in Xenopus oocytes cannot mediate Cl^–/HCO₃^– exchange or ³⁶Cl^– efflux but exhibits enhanced dual sulfate efflux mechanisms: electroneutral exchange of intracellular sulfate for extracellular sulfate (SO₄^2–_i/SO₄^2–_o exchange), and electrogenic exchange of intracellular sulfate for extracellular chloride (SO₄^2–_i/Cl^–_o exchange). Whereas wild-type AE1 mediates 1:1 H⁺/SO₄^2– cotransport in exchange for either Cl^– or for the H⁺/SO₄^2– ion pair, mutant Ae1 E699Q transports sulfate without cotransport of protons, similar to human erythrocyte AE1 in which the corresponding E681 carboxylate has been chemically converted to the alcohol (hAE1 E681OH). We now show that in contrast to the normal cis-stimulation by protons of wild-type AE1-mediated SO₄^2– transport, both SO₄^2–_i/Cl^–_o exchange and SO₄^2–_i/SO₄^2–_o exchange mediated by mutant Ae1 E699Q are inhibited by acidic pH_o and activated by alkaline pH_o. hAE1 E681OH displays a similarly altered pH_o dependence of SO₄^2–_i/Cl^–_o exchange. Elevated [SO₄^2–]_i increases the K_1/2 of Ae1 E699Q for both extracellular Cl^– and SO₄^2–, while reducing inhibition of both exchange mechanisms by acid pH_o. The E699Q mutation also leads to increased potency of self-inhibition by extracellular SO₄^2–. Study of the Ae1 E699Q mutation has revealed the existence of a novel pH-regulatory site of the Ae1 polypeptide and should continue to provide valuable paths toward understanding substrate selectivity and self-inhibition in SLC4 anion transporters.

band 3; 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid; Xenopus oocyte; Woodward's reagent K

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				S. L. Alper Molecular physiology and genetics of Na+-independent SLC4 anion exchangers J. Exp. Biol., June 1, 2009; 212(11): 1672 - 1683. [Abstract] [Full Text] [PDF]