Untitled

Abstract

(2S,1'S,2'R)-2-(Carboxycyclopropyl)glycine (L-CCG III) was a substrate of Na(+)-dependent glutamate transporters (GluT) in Xenopus laevis oocytes (IC50 to approximately 13 and to approximately 2 microM for, respec tively, EAAT 1 and EAAT 2) and caused an apparent inhibition of [3H]L-glutamate uptake in "mini-slices" of guinea pig cerebral cortex (IC50 to approximately 12 microM). In slices (350 microM) of guinea pig cerebral cortex, 5 microM L-CCG III increased both the flux of label through pyruvate carboxylase and the fractional enrichment of glutamate, GABA, glutamine and lactate, but had no effect on total metabolite pool sizes. At 50 microM L-CCG III decreased incorporation of 13C from [3-13C]-pyruvate into glutamate C4, glutamine C4, lactate C3 and alanine C3. The total metabolite pool sizes were also decreased with no change in the fractional enrichment. Furthermore, L-CCG III was accumulated in the tissue, probably via GluT. At lower concentration, L-CCG III would compete with L-glutamate for GluT and the changes probably reflect a compensation for the "missing" L-glutamate. At 50 microM, intracellular L-CCG III could reach > 10 mM and metabolism might be affected directly.

Distribution of Glutamate Transporter GLAST in Membranes of Cultured Astrocytes in the Presence of Glutamate Transport Substrates and ATP

“…Such movements may occur in response to changes in the activity of glutamatergic synapses and, therefore, activity of L-glu transport could be of importance not only for the normal operation of the synaptic excitation [5] but also as an indicator of local excitatory activity that would have to be matched by local changes in the metabolism and blood flow. Indeed, it has recently been demonstrated that not only pharmacological manipulation of glutamate receptors but, in particular, interference with GluT, can elicit specific metabolic responses in brain tissue [14][15][16][17].…”

Rottlerin Inhibits (Na+, K+)-ATPase Activity in Brain Tissue and Alters d-Aspartate Dependent Redistribution of Glutamate Transporter GLAST in Cultured Astrocytes

“…)-dependent ATPase in brain tissue [13]. Such a relationship could be important for the regulation of energy supply in response to changes in excitatory (glutamatergic) synaptic activity [14,15] and for the activity of metabolic pathways that are linked to glutamatergic neurotransmission and/or to functioning glutamate transport [16][17][18]. Testing the effect of rottlerin on the activity of the (Na ?…”

Fragmental Modeling of Human Glutamate Transporter EAAT1 and Analysis of its Binding Modes by Docking and Pharmacophore Mapping

“…In particular, this set includes the l-glutamate [42] (1) and both enantiomers of aspartate [43] (2, 3) as natural substrates. As substrate inhibitors the set includes: 4-methylglutamate isomers (4)(5), [42] l-threo-b-hydroxyaspartate (THA, 6), [6] l-threo-4-hydroxyglutamate (7), [42] l-sulphate-O-serine (l-SOS, 8), [9] three cyclopropyl derivatives (namely, l-CCG-III, 9, d-CCG-I, 10, and l-CCG-IV, 11), [44] four pyrrolidine dicarboxylates (namely, t-2,4 PDC, 12, 2,4MPDC, 13, l-3,4MPDC, 14, 4-Methyl-2,4 PDC, 15), [42] and cis-aminocyclobutyl dicarboxylate (cis-ABCD, 16). [9] Figure 2 includes the nontransported blockers which can be divided in three main groups: b-hydroxyaspartate derivatives (17)(18)(19)(20)(21)(22)(23)(24)(25)(26), [45,46] aspartic acid amides (27)(28)(29)(30), [47] and diaminopropionic acid analogues (DAPAs, 31-32).…”