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J. Biol. Chem., Vol. 280, Issue 9, 8564-8580, March 4, 2005

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Functional Comparison of Mouse slc26a6 Anion Exchanger with Human SLC26A6 Polypeptide Variants

DIFFERENCES IN ANION SELECTIVITY, REGULATION, AND ELECTROGENICITY^*

Marina N. Chernova, Lianwei Jiang, David J. Friedman, Rachel B. Darman, Hannes Lohi¶, Juha Kere¶||, David H. Vandorpe, and Seth L. Alper**

From the Molecular and Vascular Medicine Unit and Renal Unit, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, the ^¶Department of Genetics, University of Helsinki, 00014 Helsinki, Finland, and the ^||Department of Biosciences, Karolinska Institute, 14157 Huddinge, Sweden

The unusually low 78% amino acid identity between the orthologous human SLC26A6 and mouse slc26a6 polypeptides prompted systematic comparison of their anion transport functions in Xenopus oocytes. Multiple human SLC26A6 variant polypeptides were also functionally compared. Transport was studied as unidirectional fluxes of ³⁶Cl^-, [¹⁴C]oxalate, and [³⁵S]sulfate; as net fluxes of by fluorescence ratio measurement of intracellular pH; as current by two-electrode voltage clamp; and as net Cl^- flux by fluorescence intensity measurement of relative changes in extracellular and intracellular [Cl^-]. Four human SLC26A6 polypeptide variants each exhibited rates of bidirectional [¹⁴C]oxalate flux, exchange, and Cl^-/OH^- exchange nearly equivalent to those of mouse slc26a6. exchange by both orthologs was cAMP-sensitive, further enhanced by coexpressed wild type cystic fibrosis transmembrane regulator but inhibited by cystic fibrosis transmembrane regulator F508. However, the very low rates of ³⁶Cl^- and [³⁵S]sulfate transport by all active human SLC26A6 isoforms contrasted with the high rates of the mouse ortholog. Human and mouse orthologs also differed in patterns of acute regulation. Studies of human-mouse chimeras revealed cosegregation of the high ³⁶Cl^- transport phenotype with the transmembrane domain of mouse slc26a6. Mouse slc26a6 and human SLC26A6 each mediated electroneutral and Cl^-/OH^- exchange. In contrast, whereas Cl^-/oxalate exchange by mouse slc26a6 was electrogenic, that mediated by human SLC26A6 appeared electroneutral. The increased currents observed in oocytes expressing either mouse or human ortholog were pharmacologically distinct from the accompanying monovalent anion exchange activities. The human SLC26A6 polypeptide variants SLC26A6c and SLC26A6d were inactive as transporters of oxalate, sulfate, and chloride. Thus, the orthologous mouse and human SLC26A6 proteins differ in anion selectivity, transport mechanism, and acute regulation, but both mediate electroneutral exchange.

Received for publication, October 14, 2004 , and in revised form, November 11, 2004.

^* This work was supported by National Institutes of Health Grants DK43495 and 34854 (to S. L. A.) and HL73112 (to D. H. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains an additional figure and table.

A postdoctoral fellow of the American Heart Association New England Region.

^** To whom correspondence should be addressed: E/RW-763 Beth Israel Deaconess Med. Ctr., 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-2930; Fax: 617-667-8040; E-mail: salper{at}bidmc.harvard.edu.

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