Endogenous gamma-L-glutamylglutamate is a partial agonist at the N-methyl-D-aspartate receptors in cultured cerebellar granule cells.
gamma-L-Glutamylglutamate (LGG), an endogenous constituent of the brain, reduced the glutamate-evoked increase in intracellular Ca2+ in cultured cerebellar granule cells. The extent and properties of this inhibition were different at different Mg2+ concentrations. The intracellular Ca2+ response to NMDA was slightly enhanced by 0.1 mM LGG in normal (1.3 mM) Mg2+ medium, but in Mg(2+)-free medium LGG was stimulatory at low (0.1-1 microM) NMDA and inhibitory at high (0.1-1 mM) NMDA concentrations. In the absence of Mg2+, LGG alone increased cytosolic free Ca2+ and depolarized the cells. These effects were potentiated by glycine and blocked by extracellular Mg2+, 2-amino-5-phosphonopentanoate (APV), 7-chlorokynurenate, 3-amino-1-hydroxypyrrolidin-2-one (HA-966) and 5,7-dinitroquinoxaline-2,3-dione (MNQX). The results indicate that LGG is a partial NMDA agonist. On the other hand, the non-NMDA antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6,7-dinitroquinoxaline-2,3-dione (DNQX) also inhibited the effects of LGG. This indicates an involvement of non-NMDA receptors in the actions of LGG. The consequent depolarization may also contribute to the activation of NMDA receptor-governed ionophores.
Varga
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V
Department of Physiology, University of Tampere Medical School, Finland.
Janáky
R
R
Holopainen
I
I
Oja
S S
SS
Akerman
K E
KE
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology*; D004357:Drug Synergism; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology
D004151:Dipeptides; D005971:Glutamates; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C082810:gamma-glutamylglutamate; C063295:5,7-dinitroquinoxaline-2,3-dione; D018698:Glutamic Acid; C056723:FG 9041; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D008274:Magnesium; D002118:Calcium; D005998:Glycine