The sodium-dependent di- and tricarboxylate transporter, NaCT, is not responsible for the uptake of D-, L-2-hydroxyglutarate and 3-hydroxyglutarate into neurons.
Concentrations of glutarate (GA) and its derivatives such as 3-hydroxyglutarate (3OHGA), D- (D-2OHGA) and L-2-hydroxyglutarate (L-2OHGA) are increased in plasma, cerebrospinal fluid (CSF) and urine of patients suffering from different forms of organic acidurias. It has been proposed that these derivatives cause neuronal damage in these patients, leading to dystonic and dyskinetic movement disorders. We have recently shown that these compounds are eliminated by the kidneys via the human organic anion transporters, OAT1 and OAT4, and the sodium-dependent dicarboxylate transporter 3, NaDC3. In neurons, where most of the damage occurs, a sodium-dependent citrate transporter, NaCT, has been identified. Therefore, we investigated the impact of GA derivatives on hNaCT by two-electrode voltage clamp and tracer uptake studies. None of these compounds induced substrate-associated currents in hNaCT-expressing Xenopus laevis oocytes nor did GA derivatives inhibit the uptake of citrate, the prototypical substrate of hNaCT. In contrast, D- and L-2OHGA, but not 3OHGA, showed affinities to NaDC3, indicating that D- and L-2OHGA impair the uptake of dicarboxylates into astrocytes thereby possibly interfering with their feeding of tricarboxylic acid cycle intermediates to neurons.
Zentrum Physiologie und Pathophysiologie, Abt. Vegetative Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Göttingen, Germany.
Katja
K
Brauburger
Gerhard
G
Burckhardt
Birgitta C
BC
Burckhardt
D000818:Animals; D001692:Biological Transport; D004594:Electrophysiology / Q000379:methods; D005977:Glutarates / Q000097:blood / Q000134:cerebrospinal fluid / Q000737:chemistry* / Q000652:urine; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D009474:Neurons / Q000378:metabolism; D009865:Oocytes / Q000166:cytology; D018408:Patch-Clamp Techniques; D018075:RNA, Complementary / Q000378:metabolism; D027981:Symporters / Q000737:chemistry* / Q000378:metabolism; D014158:Transcription, Genetic; D014982:Xenopus laevis
C108959:3-hydroxyglutaric acid; D005977:Glutarates; D018075:RNA, Complementary; C470492:SLC13A5 protein, human; D027981:Symporters; C019417:alpha-hydroxyglutarate; C035736:glutaric acid
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