Trans-inhibition of glutamate transport prevents excitatory amino acid-induced glycolysis in astrocytes

Previous studies have demonstrated that activation of glutamate transporter s promotes glycolysis in astrocytes. Current evidence indicates that compou nds such as threo-beta-hydroxyaspartate (THA) are both competitive inhibito rs and substrates for glutamate transporters. In this study, we have analyz ed the effect of THA on excitatory amino acid (EAA) transport and on EAA-in duced glycolysis in mouse primary astrocyte cultures. In agreement with pre vious studies in rat astrocytes, THA competitively inhibited H-3-D-aspartat e (H-3-D-Asp) uptake with an IC50 of 319 mu M (K-i = 36.6 mu M). In contras t, it did not prevent D-aspartate-induced H-3-2-deoxyglucose (2DG) uptake i n these conditions. Preexposure of cells to THA for at least 15 min reveale d another form of glutamate transport inhibition. This effect was concentra tion-dependent with an apparent IC50 of 47.7 mu M and showed kinetic charac teristics consistent with a mechanism of trans-inhibition. Preincubation wi th THA also inhibited D-aspartate-induced H-3-2DG uptake in a concentration -dependent manner with an apparent IC50 of 59.8 mu M. Comparison with other transportable analogues reveals that they share with THA the ability to ca use trans-inhibition of glutamate transport and to prevent glutamate-stimul ated glycolysis; THA, however, is unique in that it has no effect alone on glucose utilization after preexposure. These data indicate that trans-inhib ition of glutamate transport may be a mechanism by which certain glutamate transport inhibitors can prevent the stimulation of aerobic glycolysis by g lutamate in astrocytes. (C) 1999 Published by Elsevier Science B.V. All rig hts reserved.