(R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors mediate a calcium-dependent inhibition of the metabotropic glutamate receptor-stimulated formation of inositol 1,4,5-trisphosphate.

L-glutamate (3-1,000 microM) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD; 10-1,000 microM), a selective agonist for the metabotropic glutamate receptor, stimulated the formation of inositol 1,4,5-trisphosphate in a concentration-dependent manner. L-Glutamate was half as efficacious as 1S,3R-ACPD. N-methyl-D-aspartate (NMDA; 1 nM to 1 mM) did not significantly influence the response to a maximally effective concentration of 1S,3R-ACPD (100 microM). On the other hand, coapplication of (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA; 1-300 nM) produced a concentration- and time-dependent inhibition of the 1S,3R-ACPD effect, with a maximal inhibition (97%) at 100 nM. Ten micromolar 6-cyano-7-nitroquinoxaline-2,3-dione, an antagonist of the AMPA receptor, blocked the inhibitory effect of AMPA. Reduced extracellular calcium concentration, as well as 10 microM nimodipine, an L-type calcium channel antagonist, inhibited the AMPA influence on the 1S,3R-ACPD response. W-7, a calcium/calmodulin antagonist, prevented the inhibition by AMPA, whereas H-7, an inhibitor of protein kinase C, had no effect. These data suggest that activation of AMPA receptors has an inhibitory influence on inositol 1,4,5-trisphosphate formation mediated by stimulation of the metabotropic glutamate receptor. The mechanism of action involves calcium influx through L-type type calcium channels and possible activation of calcium/calmodulin-dependent enzymes.