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Am J Physiol Cell Physiol 278: C1019-C1030, 2000;
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Vol. 278, Issue 5, C1019-C1030, May 2000

Structure, function, and genomic organization of human Na+-dependent high-affinity dicarboxylate transporter

Haiping Wang1, You-Jun Fei1, Ramesh Kekuda1, Teresa L. Yang-Feng2, Lawrence D. Devoe3, Frederick H. Leibach1, Puttur D. Prasad3, and Vadivel Ganapathy1

Departments of 1 Biochemistry and Molecular Biology, and 3 Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia 30912; and 2 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510

We have cloned and functionally characterized the human Na+-dependent high-affinity dicarboxylate transporter (hNaDC3) from placenta. The hNaDC3 cDNA codes for a protein of 602 amino acids with 12 transmembrane domains. When expressed in mammalian cells, the cloned transporter mediates the transport of succinate in the presence of Na+ [concentration of substrate necessary for half-maximal transport (Kt) for succinate = 20 ± 1 µM]. Dimethylsuccinate also interacts with hNaDC3. The Na+-to-succinate stoichiometry is 3:1 and concentration of Na+ necessary for half-maximal transport (KNa+0.5) is 49 ± 1 mM as determined by uptake studies with radiolabeled succinate. When expressed in Xenopus laevis oocytes, hNaDC3 induces Na+-dependent inward currents in the presence of succinate and dimethylsuccinate. At a membrane potential of -50 mV, KSuc0.5 is 102 ± 20 µM and KNa+0.5 is 22 ± 4 mM as determined by the electrophysiological approach. Simultaneous measurements of succinate-evoked charge transfer and radiolabeled succinate uptake in hNaDC3-expressing oocytes indicate a charge-to-succinate ratio of 1:1 for the transport process, suggesting a Na+-to-succinate stoichiometry of 3:1. pH titration of citrate-induced currents shows that hNaDC3 accepts preferentially the divalent anionic form of citrate as a substrate. Li+ inhibits succinate-induced currents in the presence of Na+. Functional analysis of rat-human and human-rat NaDC3 chimeric transporters indicates that the catalytic domain of the transporter lies in the carboxy-terminal half of the protein. The human NaDC3 gene is located on chromosome 20q12-13.1, as evidenced by fluorescent in situ hybridization. The gene is >80 kbp long and consists of 13 exons and 12 introns.

human placenta; electrophysiology; chromosomal localization; exon-intron organization


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