(2 S,3 S,4 R)-2-(Carboxycyclopropyl)glycine, a potent and competitive inhibitor of both glial and neuronal uptake of glutamate

Abstract

The effects of several diastereoisomers of L-2-(carboxycyclopropyl)glycine (CCG) on L-glutamate uptake were compared among three different preparations, glial plasmalemmal vesicles (GPV), synaptosomes and cultured astrocytes from rat hippocampus. The (2 S,3 S,4 R)-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 potency was quite similar to that of L- threo-β-hydroxyaspartate in both subcellular fractions and much higher than L-aspartate-β-hydroxamate, which were known as potent inhibitors of glutamate uptake. The (2 S,3 S,4 R)-isomer ( L-CCG-IV) also inhibited the glutamate uptake in GPV and synaptosomes, but it was about 100 times less active than L-CCG-III. The (2 S,3 S,4 R)- and (2 S,3 R,4 R)-isomers ( L-CCG-I and L-CCG-II, respectively) hardly showed any inhibitory action on the glutamate uptake. Dixon plot analysis of the initial uptake rate revealed that the inhibition was in a competitive manner and the value of the inhibition constant ( K i ) was about 1 μM in both GPV and synaptosomes. L-CCG-III effectively inhibited the glutamate uptake by cultured hippocampal astrocytes as well. These results suggested that L-CCG-III inhibited the glutamate uptake in both neurones and glial cells of the mammalian central nervous system in a similar manner.