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J Biol Chem, Vol. 273, Issue 30, 18923-18929, July 24, 1998

Sodium and Lithium Interactions with the Na⁺/Dicarboxylate Cotransporter

Ana M. Pajor, Bruce A. Hirayama^¶, and Donald D. F. Loo^¶

From the  Department of Physiology, University of Arizona, Tucson, Arizona 85724 and the ^¶ Department of Physiology, UCLA School of Medicine, Los Angeles, California 90095-1751

The two-electrode voltage clamp was used to study the currents associated with transport of succinate by the cloned Na⁺/dicarboxylate cotransporter, NaDC-1, expressed in Xenopus oocytes. The presence of succinate induced inward currents which were dependent on the concentrations of succinate and sodium, and on the membrane potential. At 50 mV, the K_0.5^succinate was 180 µM and the K_0.5^Na+ was 19 mM. The Hill coefficient was 2.3, which is consistent with a transport stoichiometry of 3 Na⁺:1 divalent anion substrate. Currents were induced in NaDC-1 by a range of di- and tricarboxylates, including citrate, methylsuccinate, fumarate, and tricarballylate. Although Na⁺ is the preferred cation, Li⁺ was also able to support transport. The K_0.5^succinate was approximately 10-fold higher in Li⁺ compared with Na⁺. In the presence of Na⁺, however, Li⁺ was a potent inhibitor of transport. Millimolar concentrations of Li⁺ resulted in decreases in apparent succinate affinity and in the I_max^succinate. Furthermore, lithium inhibition under saturating sodium concentrations showed hyperbolic kinetics, suggesting that one of the three cation binding sites in NaDC-1 has a higher affinity for Li⁺ than Na⁺. We conclude that NaDC-1 is an electrogenic anion transporter that accepts either Na⁺ or Li⁺ as coupling cations. However, NaDC-1 contains a single high affinity binding site for Li⁺ that, when occupied, results in transport inhibition, which may account for its potent inhibitory effects on renal dicarboxylate transport.

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