(2S,3S,4R)-2-(CARBOXYCYCLOPROPYL)GLYCINE, A POTENT AND COMPETITIVE INHIBITOR OF BOTH GLIAL AND NEURONAL UPTAKE OF GLUTAMATE

The effects of several diastereoisomers of L-2-(carboxycyclopropyl)gly cine (CCG) on L-glutamate uptake were compared among three different p reparations, glial plasmalemmal vesicles (GPV), synaptosomes and cultu red astrocytes from rat hippocampus. The (2S,3S,4R)-isomer (L-CCG-III) inhibited a Na+-dependent high-affinity L-glutamate uptake in GPV and synaptosomes in a dose dependent manner at a micromolar range. The po tency was quite similar to that Of L-threo-beta-hydroxyaspartate in bo th subcellular fractions and much higher than L-aspartate-beta-hydroxa mate, which were known as potent inhibitors of glutamate uptake. The ( 2S,3R,4S)-isomer (L-CCG-IV) also inhibited the glutamate uptake in GPV and synaptosomes, but it was about 100 times less active than L-CCG-I II. The (2S,3S,4S)-and (2S,3R,4R)-isomers (L-CCG-I and L-CCG-II, respe ctively) hardly showed any inhibitory action on the glutamate uptake. Dixon plot analysis of the initial uptake mte revealed that the inhibi tion was in a competitive manner and the value of the inhibition const ant (K(i)) was about 1 muM in both GPV and synaptosomes. L-CCG-III eff ectively inhibited the glutamate uptake by cultured hippocampal astroc ytes as well. These results suggested that L-CCG-III inhibited the glu tamate uptake in both neurones and glial cells of the mammalian centra l nervous system in a similar manner.