(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)glycine (CCG) on L-glutamate uptake were compared among three different preparations, glial plasmalemmal vesicles (GPV), synaptosomes and cultured 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 potency was quite similar to that of L-threo-beta-hydroxyaspartate in both subcellular fractions and much higher than L-aspartate-beta-hydroxamate, 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-III. The (2S,3S,4S)- and (2S,3R,4R)-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 (Ki) was about 1 microM 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.
Nakamura
Y
Y
Department of Physiology, Ehime University, School of Medicine, Japan.
Kataoka
K
K
Ishida
M
M
Shinozaki
H
H
D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001216:Asparagine / Q000031:analogs & derivatives / Q000494:pharmacology; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003864:Depression, Chemical; D005260:Female; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D006624:Hippocampus / Q000378:metabolism / Q000648:ultrastructure; D007700:Kinetics; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000600:Amino Acids, Dicarboxylic; D000900:Anti-Bacterial Agents; D005971:Glutamates; C011274:3-hydroxyaspartic acid; C024848:beta-aspartylhydroxamic acid; C035261:(alpha-carboxycyclopropyl)glycine; D001224:Aspartic Acid; D018698:Glutamic Acid; D001216:Asparagine