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The Effects of l ‐Glutamate and trans ‐(±)‐1‐Amino‐1,3‐Cyclopentanedicarboxylate on Phosphoinositide Hydrolysis Can Be Pharmacologically Differentiated
Author(s) -
Littman Louis,
Robinson Michael B.
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.63041291.x
Subject(s) - chemistry , hydrolysis , glutamate receptor , biochemistry , stereochemistry , receptor
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 pre‐incubated with l ‐AP3, the effects of l ‐Glu, l ‐Asp, or d ‐Asp were blocked (IC 50 values between 65 and 210 µ M ). Unlike l ‐AP3, l ‐aspartate‐β‐hydroxamate ( l ‐AβHA) 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 ‐AβHA had agonist activity. Inhibition by the recently identified competitive inhibitor (+)‐α‐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 (IC 50 values between 220 and 1,700 µ M ). The effects of (+)‐MCPG were consistent with a competitive mechanism of action. (+)‐MCPG (up to 3 m M ) blocked PI hydrolysis stimulated by l ‐Glu by less than 25% in both hippocampus and cerebellum.