(R,S)‐α‐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

Abstract: l‐Glutamate (3‐1,000 μM) and (1S,3R)‐l‐aminocyclopentane‐1,3‐dicarboxylic acid (1S.3R‐ACPD; 10‐1,000 μM), 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 μM). On the other hand, coapplication of (R,S)‐α‐amino‐3‐hydroxy‐5‐methylisoxa‐zole‐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 μM 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 calcium channels and possible activation of calcium/calmodulin‐dependent enzymes.