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-(+-)-1-amino-1,3-cyclopentanedicarboxylate (trans-ACPD) stimulate the hydrolysis of phosphoinositides (PI). In the present studies, the effects of noncompetitive and competitive inhibitors on PI hydrolysis stimulated by excitatory amino acid analogues were examined. When agonist and inhibitor were added simultaneously to hippocampal tissue, the noncompetitive inhibitor L-2-amino-3-phosphonopropionate (L-AP3) did not block the effects of L-Glu, L-Asp, or D-Asp at 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 microM). Unlike L-AP3, L-aspartate-beta-hydroxamate (L-A beta HA) inhibited PI hydrolysis stimulated by trans-ACPD, L-Glu, L-Asp, or D-Asp when agonist and inhibitor were added simultaneously in hippocampus; its effects were not time-dependent. In cerebellum, both L-AP3 and L-A beta HA had agonist activity. Inhibition by the recently identified competitive inhibitor (+)-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 microM). The effects of (+)-MCPG were consistent with a competitive mechanism of action. (+)-MCPG (up to 3 mM) blocked PI hydrolysis stimulated by L-Glu by less than 25% in both hippocampus and cerebellum.