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Differential interaction of dicarboxylates with human sodium-dicarboxylate cotransporter 3 and organic anion transporters 1 and 3.
Organic anions are taken up from the blood into proximal tubule cells by organic anion transporters 1 and 3 (OAT1 and OAT3) in exchange for dicarboxylates. The released dicarboxylates are recycled by the sodium dicarboxylate cotransporter 3 (NaDC3). In this study, we tested the substrate specificities of human NaDC3, OAT1, and OAT3 to identify those dicarboxylates for which the three cooperating transporters have common high affinities. All transporters were stably expressed in HEK293 cells, and extracellularly added dicarboxylates were used as inhibitors of [(14)C]succinate (NaDC3), p-[(3)H]aminohippurate (OAT1), or [(3)H]estrone-3-sulfate (OAT3) uptake. Human NaDC3 was stably expressed as proven by immunochemical methods and by sodium-dependent uptake of succinate (K(0.5) for sodium activation, 44.6 mM; Hill coefficient, 2.1; K(m) for succinate, 18 μM). NaDC3 was best inhibited by succinate (IC(50) 25.5 μM) and less by α-ketoglutarate (IC(50) 69.2 μM) and fumarate (IC(50) 95.2 μM). Dicarboxylates with longer carbon backbones (adipate, pimelate, suberate) had low or no affinity for NaDC3. OAT1 exhibited the highest affinity for glutarate, α-ketoglutarate, and adipate (IC(50) between 3.3 and 6.2 μM), followed by pimelate (18.6 μM) and suberate (19.3 μM). The affinity of OAT1 to succinate and fumarate was low. OAT3 showed the same dicarboxylate selectivity with ∼13-fold higher IC(50) values compared with OAT1. The data 1) reveal α-ketoglutarate as a common high-affinity substrate of NaDC3, OAT1, and OAT3 and 2) suggest potentially similar molecular structures of the binding sites in OAT1 and OAT3 for dicarboxylates.
Abteilung Vegetative Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Göttingen, Germany., , , , , , , ,
MeSHAmino Acid Sequence
Dicarboxylic Acid Transporters
Electrophoresis, Polyacrylamide Gel
Molecular Sequence Data
Organic Anion Transport Protein 1
Organic Anion Transporters, Sodium-Dependent
Organic Anion Transporters, Sodium-Independent
Pub Type(s)Journal Article
Research Support, Non-U.S. Gov't