THE EFFECTS OF L-GLUTAMATE AND TRANS-(+ -)-1-AMINO-1,3-CYCLOPENTANEDICARBOXYLATE ON PHOSPHOINOSITIDE HYDROLYSIS CAN BE PHARMACOLOGICALLY DIFFERENTIATED/

The excitatory amino acid analogues L-glutamate (L-Glu), L-aspartate ( L-Asp), D-Asp, and trans-(+/-)-lamino-1,3-cyclopentanedicarboxylate (t rans-ACPD) stimulate the hydrolysis of phosphoinositides (PI). In the present studies, the effects of noncompetitive and competitive inhibit ors on PI hydrolysis stimulated by excitatory amino acid analogues wer e examined. When agonist and inhibitor were added simultaneously to hi ppocampal tissue, the noncompetitive inhibitor L-2-amino-3-phosphonopr opionate (L-AP3) did not block the effects of L-Glu, L-Asp, or D-Asp a t concentrations that block the effects of trans-ACPD by more than 80% . When tissue was preincubated with L-AP3, the effects of L-Glu, L-Asp , or D-Asp were blocked (IC50 values between 65 and 210 mu M). Unlike L-AP3, L-aspartate-beta-hydroxamate (L-A beta HA) inhibited PI hydroly sis stimulated by trans-ACPD, L-Glu, L-Asp, or D-Asp when agonist and inhibitor were added simultaneously in hippocampus; its effects were n ot time-dependent. In cerebellum, both L-AP3 and L-A beta HA had agoni st activity. Inhibition by the recently identified competitive inhibit or (+)-alpha-methyl-4-carboxyphenylglycine [(+)-MCPG] of PI hydrolysis was also examined. (+)MCPG blocked PI hydrolysis stimulated by trans- ACPD, L-Asp, or D-Asp in both hippocampus and cerebellum (IC50 values between 220 and 1,700 mu M). The effects of (+)-MCPG were consistent w ith a competitive mechanism of action. (+)-MCPG (up to 3 mM) blocked P I hydrolysis stimulated by L-Glu by less than 25% in both hippocampus and cerebellum.