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J Mol Med (Berl)
2007 Jul 01;857:763-70. doi: 10.1007/s00109-007-0174-5.
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3-Hydroxyglutaric acid is transported via the sodium-dependent dicarboxylate transporter NaDC3.
Stellmer F
,
Keyser B
,
Burckhardt BC
,
Koepsell H
,
Streichert T
,
Glatzel M
,
Jabs S
,
Thiem J
,
Herdering W
,
Koeller DM
,
Goodman SI
,
Lukacs Z
,
Ullrich K
,
Burckhardt G
,
Braulke T
,
Mühlhausen C
.
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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, kidneytissue 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 K (M) 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.
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