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J. Biol. Chem., Vol. 283, Issue 19, 12777-12788, May 9, 2008

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Characterization of Human SLC4A10 as an Electroneutral Na/HCO₃ Cotransporter (NBCn2) with Cl^– Self-exchange Activity^*

From the Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut 06520

The SLC4A10 gene product, commonly known as NCBE, is highly expressed in rodent brain and has been characterized by others as a Na⁺-driven Cl-HCO₃ exchanger. However, some of the earlier data are not consistent with Na⁺-driven Cl-HCO₃ exchange activity. In the present study, northern blot analysis showed that, also in humans, NCBE transcripts are predominantly expressed in brain. In some human NCBE transcripts, splice cassettes A and/or B, originally reported in rats and mice, are spliced out. In brain cDNA, we found evidence of a unique partial splice of cassette B that is predicted to produce an NCBE protein with a novel C terminus containing a protein kinase C phosphorylation site. We used pH-sensitive microelectrodes to study the molecular physiology of human NCBE expressed in Xenopus oocytes. In agreement with others we found that NCBE mediates the 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid-sensitive, Na⁺-dependent transport of . For the first time, we demonstrated that this transport process is electroneutral. Using Cl^–-sensitive microelectrodes positioned at the oocyte surface, we found that, unlike both human and squid Na⁺-driven Cl-HCO₃ exchangers, human NCBE does not normally couple the net influx of to a net efflux of Cl^–. Moreover we found that that the ³⁶Cl efflux from NCBE-expressing oocytes, interpreted by others to be coupled to the influx of Na⁺ and , actually represents a -stimulated Cl^– self-exchange not coupled to either Na⁺ or net transport. We propose to rename NCBE as the second electroneutral Na/HCO₃ cotransporter, NBCn2.

Received for publication, September 19, 2007 , and in revised form, February 29, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant NS18400. 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 supplemental material including Table 1 and Figs. 1–4.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY376402.

¹ Both authors contributed equally to this work.

² Present address: Dept. of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106.

³ Supported by American Heart Association Fellowship 0625891T.

⁴ Present address: Dept. of Respiratory Care, University of Texas Medical Branch, Galveston, TX 77555.

⁵ Present address: Dept. of Physiology, Emory University School of Medicine, Atlanta, GA 30322.

⁶ To whom correspondence should be addressed: Dept. of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106. Tel.: 216-368-3400; Fax: 216-368-5586; E-mail: wfb2{at}case.edu.

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