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J Biol Chem, Vol. 273, Issue 33, 20972-20981, August 14, 1998
From the Renal Division, Brigham and Women's Hospital, Harvard
Medical School, Boston, Massachusetts 02115
The metabolism of Krebs cycle intermediates is of
fundamental importance for eukaryotic cells. In the kidney, these
intermediates are transported actively into epithelial cells. Because
citrate is a potent inhibitor for calcium stone formation, excessive
uptake results in nephrolithiasis due to hypocitraturia. We report the cloning and characterization of a rat kidney dicarboxylate transporter (SDCT1). In situ hybridization revealed that SDCT1 mRNA
is localized in S3 segments of kidney proximal tubules and in
enterocytes lining the intestinal villi. Signals were also detected in
lung bronchioli, the epididymis, and liver. When expressed in
Xenopus oocytes, SDCT1 mediated electrogenic,
sodium-dependent transport of most Krebs cycle
intermediates (Km = 20-60 µM),
including citrate, succinate, 
-ketoglutarate, and oxaloacetate. Of
note, the acidic amino acids L- and D-glutamate
and aspartate were also transported, although with lower affinity
(Km = 2-18 mM). Transport of citrate
was pH-sensitive. At pH 7.5, the Km for citrate was
high (0.64 mM), whereas at pH 5.5, the
Km was low (57 µM). This is
consistent with the concept that the 
2 form of citrate is the
transported species. In addition, maximal currents at pH 5.5 were 70%
higher than those at pH 7.5, and our data show that the 3 form acts
as a competitive inhibitor. Simultaneous measurements of
substrate-evoked currents and tracer uptakes under voltage-clamp
condition, as well as a thermodynamic approach, gave a Na+
to citrate or a Na+ to succinate stoichiometry of 3 to 1. SDCT1-mediated currents were inhibited by phloretin. This plant
glycoside also inhibited the SDCT1-specific sodium leak in the absence
of substrate, indicating that at least one Na+ binds to the
transporter before the substrate. The data presented provide new
insights into the biophysical characteristics and physiological
implications of a cloned dicarboxylate transporter.
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