The effect of lithium salts on the urinary excretion of α‐oxoglutarate in man

Bond, P.A.; Jenner, F. A.; Lee, C. R.; Lenton, Elizabeth A.; Pollitt, R. J.; Sampson, Gwyneth A.

doi:10.1111/j.1476-5381.1972.tb06854.x

Cited by 23 publications

(16 citation statements)

References 19 publications

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“…Lithium also acts as a potent inhibitor of succinate transport by NaDC-1 when Na ϩ is present, with an apparent K i of 2 mM (3,11). In humans and rodents, treatment with Li ϩ leads to rapid increases in urinary concentrations of Krebs cycle intermediates (4,27). In this study, Li ϩ behaved as a mixed-type inhibitor of NaDC-1.…”

Section: Discussionmentioning

confidence: 63%

“…The Na ϩ -dicarboxylate cotransporter reabsorbs a wide range of di-and tricarboxylic acids in the form of divalent anions. This transporter is sensitive to inhibition by lithium (3), and patients receiving therapeutic doses of lithium exhibit increased renal excretion of ␣-ketoglutarate and glutarate (4). The cDNA coding for the rabbit renal Na ϩ /dicarboxylate cotransporter, NaDC-1, 1 has been cloned and sequenced (5), and the protein has been identified in renal brush border membranes (6).…”

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confidence: 99%

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Sodium and Lithium Interactions with the Na+/Dicarboxylate Cotransporter

Pajor¹,

Hirayama²,

Loo³

1998

Journal of Biological Chemistry

109

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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 M 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.The active transport of Krebs cycle intermediates, such as succinate and citrate, is mediated by a specific sodium-coupled transporter found on the apical membrane in epithelial cells of the kidney proximal tubule (1, 2). The Na ϩ -dicarboxylate cotransporter reabsorbs a wide range of di-and tricarboxylic acids in the form of divalent anions. This transporter is sensitive to inhibition by lithium (3), and patients receiving therapeutic doses of lithium exhibit increased renal excretion of ␣-ketoglutarate and glutarate (4). The cDNA coding for the rabbit renal Na ϩ /dicarboxylate cotransporter, NaDC-1, 1 has been cloned and sequenced (5), and the protein has been identified in renal brush border membranes (6). NaDC-1 belongs to a distinct gene family of sodium-coupled anion transporters that includes the Na ϩ /dicarboxylate cotransporters, hNaDC-1, from human kidney (7), and NaDC-2, from Xenopus intestine (8), and the renal Na ϩ /sulfate cotransporter, NaSi-1 (9). The transport mechanism of NaDC-1 is thought to involve the ordered binding of four charged substrates: 3 Na ϩ ions and 1 divalent anion substrate (10 -12), resulting in one net inward positive charge across the membrane per cycle. Experiments with rabbit renal brush border membrane vesicles support this hypothesis: sodium-dependent transport of succinate was affected by changes in membrane potential, and transport of succinate also caused a depolarization of membrane potential (12-14). However, the dependence of transport kinetics o...

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Section: Discussionmentioning

confidence: 63%

mentioning

confidence: 99%

Sodium and Lithium Interactions with the Na+/Dicarboxylate Cotransporter

Pajor¹,

Hirayama²,

Loo³

1998

Journal of Biological Chemistry

109

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“…5) ii from 1-sec uptakes. Note that the membranes were not voltgroup (1,3,5) that Li ihibits the active reuptake ofdicarboxylic iped in this experiment. The J vs. Li data were fitted to a modacids by the renal tubule.…”

Section: + Tmentioning

confidence: 99%

“…Within minutes, Li+ at therapeutic doses increases renal excretion of a-ketoglutarate and succinate by 1-2 orders ofmagnitude. Jenner's group (3)(4)(5) speculated that Li+ increased excretion by inhibiting the active reuptake of the dicarboxylic acids by the renal tubule.…”

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Interactions between lithium and renal transport of Krebs cycle intermediates.

Wright¹,

Wright²,

Hirayama³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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The effect of lithium on the renal transport of Krebs cycle intermediates was studied in brush border membrane vesicles isolated from the rabbit renal cortex. The di-and tricarboxylic acids are avidly transported across renal brush border membranes by a sodium cotransport system. Lithium acted as a potent, specific, competitive inhibitor (K; = 1.2 mM) of succinate/ sodium cotransport when added to the uptake medium. Similar effects were observed for citrate but not D-glucose, L-phenylalanine, L-proline, L-alanine, or L-lactate transport. Intravesicular lithium behaved as a noncompetitive inhibitor of succinate transport in the absence of sodium. These results account for the observation that therapeutic doses of lithium increase the renal excretion of Krebs cycle intermediates. The existence of a transport system for a-ketoglutarate in synaptosomes suggests a possible target for lithium in the central nervous system.Since 1949 lithium has been used successfully in the therapy of manic-depressive illness. However, there are few clues as to the site and mode of action of this psychoactive agent. One of the most striking immediate effects of Li' is on the renal excretion of Krebs cycle intermediates in both man and experimental animals (1, 2). Within minutes, Li+ at therapeutic doses increases renal excretion of a-ketoglutarate and succinate by 1-2 orders ofmagnitude. Jenner's group (3-5) speculated that Li+ increased excretion by inhibiting the active reuptake of the dicarboxylic acids by the renal tubule.Recently we (6-10) established the presence of an avid Na cotransport system for dicarboxylic acids in the brush border membrane of the renal cortex and this led us to examine the interactions of Li+ with this system. We find that Li' is a potent specific inhibitor of dicarboxylic transport, and this has important implications in both lithium therapy and the kinetics of a Na-dependent transport process. METHODSTransport experiments were carried out on rabbit renal brush border membrane vesicles as described in detail elsewhere (9,10). For most experiments the vesicles were loaded with 100 mM KC1, 5 mM Tris Hepes at pH 7.5, and sufficient mannitol to give a final osmolarity of 300-955 mosM. Rates of transport [Js mol/(mg protein x min)] were obtained from 1-to 10-sec uptakes by using radioactive isotopes obtained from New England Nuclear and a rapid filtration procedure. The final composition ofthe uptake medium was 0-450 mM in chloride salts, 100 mM KC1, 5 mM Tris Hepes at pH 7.5, and sufficient mannitol to make the solution iso-osmotic with the loading buffer. Unless otherwise noted, the electrical potential (PD) across the membrane of the vesicle was clamped at 0 mV by the addition of the ionophores valinomycin (25 pg/ml) and p-trifluoromethoxyphenylhydrazone (75 AM) (FCCP) to the loading and uptake buffers. Note that Ki = Ko and pHi = pH0, and in the presence of these ionophores the K and H conductance is high enough to shunt the PD (unpublished data).Data reduction and kinetic analysis of transport ...

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“…Previous investigations speculated that lithium increased renal excretion of dicar boxylic acids by reducing renal tubular reabsorption (13,14). Recently, Wright et al demonstrated that lithium acted as a potent inhibitor of the Na+-dependent uptake of a dicarboxylic acid, succinate, into renal luminal membrane vesicles, but did not inhibit Na+-coupled glucose and amino acid transport into the vesicles (15).…”

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confidence: 99%