Modulation of Non‐N‐Methyl‐D‐Aspartate Receptors in Cultured Cerebellar Granule Cells

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Abstract
Kainic acid (KA), quisqualic acid (QUIS), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) stimulated D-[3H]aspartate release from cultured cerebellar granule cells in a concentration-dependent way. The EC50 values were 50 μM for KA (Gallo et al., 1987) and 20 μM for both QUIS and AMPA, but the efficacy of QUIS appeared to be greater than that of AMPA. The release of D-[3H]aspartate induced by KA, QUIS, and AMPA was blocked, in a dose-dependent way, by the new glutamate receptor antagonist 6-cyano-2,3-dihydroxy-7-nitroquinoxaline (CNQX); IC50 values were 0.7 μM in the case of AMPA (50 μM) and 1 μM in the case of KA (50 μM). AMPA (50–300 μM) inhibited the effect of 50 μM KA on D-[3H]aspartate release. At 300 μM AMPA, the effect of KA plus AMPA was not antagonized by the KA receptor antagonist kynurenic acid (KYN). In contrast, when KA was used at an ineffective concentration (10 μM), the addition of AMPA at concentrations below the EC50 value (10–20 μM) resulted in a synergistic effect on D-[3H]aspartate release. In this case, the evoked release of D-[3H]aspartate was sensitive to KYN. KA stimulated the formation of cyclic GMP, whereas QUIS, AMPA, and glutamate were ineffective. The accumulation of cyclic GMP elicited by KA (100 μM) was prevented not only by the antagonists CNQX (IC50= 1.5 μM) and KYN (IC50= 200 μM), but also by the agonists AMPA (IC50= 50 μM), QUIS (IC50= 3.5 μM), and glutamate (IC50= 100 μM). We conclude that AMPA, like QUIS, may act as a partial agonist at KA receptors. Moreover, CNQX effectively antagonizes non-N-methyl-D-aspartate receptor-mediated responses in cultured cerebellar granule cells.