Journal of Molecular Medicine

, Volume 85, Issue 7, pp 763–770

3-Hydroxyglutaric acid is transported via the sodium-dependent dicarboxylate transporter NaDC3

  • Franziska Stellmer
  • Britta Keyser
  • Birgitta C. Burckhardt
  • Hermann Koepsell
  • Thomas Streichert
  • Markus Glatzel
  • Sabrina Jabs
  • Joachim Thiem
  • Wilhelm Herdering
  • David M. Koeller
  • Stephen I. Goodman
  • Zoltan Lukacs
  • Kurt Ullrich
  • Gerhard Burckhardt
  • Thomas Braulke
  • Chris Mühlhausen
Rapid Communication

DOI: 10.1007/s00109-007-0174-5

Cite this article as:
Stellmer, F., Keyser, B., Burckhardt, B.C. et al. J Mol Med (2007) 85: 763. doi:10.1007/s00109-007-0174-5

Abstract

Patients with glutaryl-CoA dehydrogenase (GCDH) deficiency accumulate glutaric acid (GA) and 3-hydroxyglutaric acid (3OH-GA) in their blood and urine. To identify the transporter mediating the translocation of 3OH-GA through membranes, kidney tissue of Gcdh−/− mice have been investigated because of its central role in urinary excretion of this metabolite. Using microarray analyses of kidney-expressed genes in Gcdh−/− mice, several differentially expressed genes encoding transporter proteins were identified. Real-time polymerase chain reaction analysis confirmed the upregulation of the sodium-dependent dicarboxylate cotransporter 3 (NaDC3) and the organic cation transporter 2 (OCT2). Expression analysis of NaDC3 in Xenopus laevis oocytes by the two-electrode-voltage-clamp technique demonstrated the sodium-dependent translocation of 3OH-GA with a KM value of 0.95 mM. Furthermore, tracer flux measurements in Chinese hamster ovary cells overexpressing OCT2 showed that 3OH-GA inhibited significantly the uptake of methyl-4-phenylpyridinium, whereas 3OH-GA is not transported by OCT2. The data demonstrate for the first time the membrane translocation of 3OH-GA mediated by NaDC3 and the cis-inhibitory effect on OCT2-mediated transport of cations.

Keywords

Glutaric aciduria type 1 Slc22a2 OCT2 Glutaryl-CoA dehydrogenase deficiency Slc13a3 NaDC3 

Abbreviations

GA1

glutaric aciduria type 1

GA

glutaric acid

Gcdh

glutaryl-CoA dehydrogenase

NaDC3

sodium-dependent dicarboxylate cotransporter 3

3OH-GA

3-hydroxyglutaric acid

OCT2

organic cation transporter 2

Slc

solute carrier

Supplementary material

109_2007_174_Fig1_ESM.jpg (179 kb)
Supplementary online Fig. 1

Co-localization of NaDC3 and Kcc4 cotransporter. Cryosections of kidney tissue of 42 day-old Gcdh−/−mice were simultaneously incubated with antibodies against NaDC3 (brown) and Kcc4 (red). Additionally, the Kcc4 localization was visualized by immunofluorescence microscopy. Arrows and arrowheads indicate basolateral and apical membranes, respectively (JPG 183 kb)

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Franziska Stellmer
    • 1
  • Britta Keyser
    • 1
  • Birgitta C. Burckhardt
    • 2
  • Hermann Koepsell
    • 3
  • Thomas Streichert
    • 4
  • Markus Glatzel
    • 5
  • Sabrina Jabs
    • 1
  • Joachim Thiem
    • 6
  • Wilhelm Herdering
    • 6
  • David M. Koeller
    • 7
  • Stephen I. Goodman
    • 8
  • Zoltan Lukacs
    • 1
    • 4
  • Kurt Ullrich
    • 1
  • Gerhard Burckhardt
    • 2
  • Thomas Braulke
    • 1
  • Chris Mühlhausen
    • 1
  1. 1.Department of PediatricsUniversity Medical Center Hamburg-EppendorfHamburgGermany
  2. 2.Center of Physiology and PathophysiologyGeorg-August-UniversityGöttingenGermany
  3. 3.Institute of Anatomy and Cell BiologyUniversity of WürzburgWürzburgGermany
  4. 4.Department of Clinical ChemistryUniversity Medical Center Hamburg-EppendorfHamburgGermany
  5. 5.Department of NeuropathologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  6. 6.Institute of Organic ChemistryUniversity of HamburgHamburgGermany
  7. 7.Department of PediatricsOregon Health and Science UniversityPortlandUSA
  8. 8.Department of PediatricsUniversity of Colorado Health Sciences CenterDenverUSA

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