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.