title: The renal Na(+)-dependent dicarboxylate transporter, NaDC-3, translocates dimethyl- and disulfhydryl-compounds and contributes to renal heavy metal detoxification.
abstract: The active transport of Krebs cycle intermediates, such as succinate, alpha-ketoglutarate, and citrate, is mediated by sodium-coupled transporters found in the luminal (NaDC-1) and basolateral plasma membranes (NaDC-3) of proximal tubule cells. This study used the two-electrode voltage clamp technique to examine steady-state currents associated with the influx of three sodium ions and one divalent dicarboxylate into oocytes expressing the sodium-dicarboxylate transporter from winter flounder kidney, fNaDC-3. The substrate concentration, where half-maximal current was observed (K(0.5)), was 30 micro M for succinate. Besides 2,2-dimethylsuccinate, fNaDC-3 also accepted 2,3-dimethylsuccinate and the oral lead-chelating agent, meso-2,3-dimercaptosuccinate (DMSA or Succimer). Whereas the K(0.5) for succinate and 2,2-dimethylsuccinate was independent of membrane voltage within -90 and -10 mV, K(0.5) for 2,3-dimethylsuccinate and 2,3-dimercaptosuccinate increased with decreasing voltage, indicating a critical role of the position of the methyl- or sulfhydryl-group in voltage-sensitive affinity. In addition to meso-2,3-dimercaptosuccinate, fNaDC-3 translocated dimercaptopropane-1-sulfonate (DMPS or Dimaval), an oral chelator for the treatment of mercury intoxication. The chelates formed by HgCl(2) and DMSA or DMPS and by Pb(NO(3))(2) and DMSA, however, were not translocated by fNaDC-3. The data suggest that NaDC-3 is an essential component in the delivery of uncomplexed antidotes for renal heavy metal detoxification.
authors.affiliation: Zentrum Physiologie und Pathophysiologie, Abteilung Vegetative Physiologie und Pathophysiologie, Georg-August Universität, Göttingen, Germany. bcburckhardt@veg-physiol.med.uni-goettingen.de
authors.forename: Birgitta C
authors.initials: BC
authors.lastname: Burckhardt
authors.forename: Britta
authors.initials: B
authors.lastname: Drinkuth
authors.forename: Christine
authors.initials: C
authors.lastname: Menzel
authors.forename: Angela
authors.initials: A
authors.lastname: König
authors.forename: Jürgen
authors.initials: J
authors.lastname: Steffgen
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Wright
authors.forename: Gerhard
authors.initials: G
authors.lastname: Burckhardt
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D029382:Dicarboxylic Acid Transporters / Q000502:physiology*; D004220:Disulfides / Q000493:pharmacokinetics; D005260:Female; D005399:Fishes; D008658:Inactivation, Metabolic / Q000502:physiology*; D007668:Kidney / Q000378:metabolism*; D019216:Metals, Heavy / Q000493:pharmacokinetics*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D004113:Succimer / Q000493:pharmacokinetics; D013386:Succinates / Q000493:pharmacokinetics*; D013451:Sulfonic Acids / Q000493:pharmacokinetics; D014494:Unithiol / Q000493:pharmacokinetics*; D014982:Xenopus laevis
chemical_list: C473111:1-propanesulfonic acid 2,3-disulfide; D029382:Dicarboxylic Acid Transporters; D004220:Disulfides; D019216:Metals, Heavy; D013386:Succinates; D013451:Sulfonic Acids; C033831:2,3-dimethylsuccinic acid; D014494:Unithiol; C473110:2,2-dimethylsuccinic acid; D004113:Succimer