Inhibition of the glutamate transporter and glial enzymes in rat striatum by the gliotoxin, alpha aminoadipate.
1. The effect of the gliotoxic analogue of glutamate, alpha aminoadipate, on the high affinity transport of D-[3H]-aspartate into a crude striatal P2 preparation, and on the activity of two enzymes of which glutamate is the substrate has been examined. 2. The L-isomer of alpha aminoadipate competitively inhibited the transport protein, with a Ki value of 192 microM, whereas the D-isomer of alpha aminoadipate was ineffective. The potent convulsant, L-methionine-S-sulphoximine, was also without effect on the activity of the glutamate transport protein. 3. L-alpha Aminoadipate was a competitive inhibitor of both glutamine synthetase, and gamma-glutamylcysteine synthetase, with Ki values of 209 microM and 7 mM respectively. Once again, the D-isomer of alpha aminoadipate was a far weaker inhibitor of either enzyme. 4. The results are discussed in terms of the mechanism of action of alpha aminoadipate in causing toxicity of glial cells.
Department of Biochemistry, University College, Belfield, Dublin, Ireland.
G J
GJ
McBean
D015074:2-Aminoadipic Acid / Q000494:pharmacology; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008717:Methionine Sulfoximine / Q000494:pharmacology; D017072:Neostriatum / Q000166:cytology / Q000201:enzymology*; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D051381:Rats; D012964:Sodium / Q000502:physiology; D013237:Stereoisomerism; D013574:Synaptosomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
D027322:Amino Acid Transport System X-AG; D006023:Glycoproteins; D008717:Methionine Sulfoximine; D015074:2-Aminoadipic Acid; D001224:Aspartic Acid; D012964:Sodium; D005974:Glutamate-Ammonia Ligase; D005721:Glutamate-Cysteine Ligase