Stimulatory effects of the putative metabotropic glutamate receptor antagonist L-AP3 on phosphoinositide turnover in neonatal rat cerebral cortex

摘要

1 The effects of the metabotropic glutamate receptor (mGluR) antagonist, L-2-amino-3-phosphono-propionate (L-AP3) on phosphoinositide turnover in neonatal rat cerebral cortex slices has been investigated. 2 At concentrations of ≤ 300 μM, L-AP3 inhibited total [~3H]-inositol phosphate ([~3H]-InsP_X) and Ins(1,4,5)P_3 mass responses stimulated by the selective mGluR agonist, 1-amino-cyclopentane-1S, 3R-dicarboxylic acid (1S, 3R-ACPD). Comparison with the competitive mGluR antagonist (± )-α-methyl-4-carboxyphenylglycine (( ± )-MCPG) clearly demonstrated that L-AP3 caused inhibition by a mechanism that was not competitive, as L-AP3 decreased the maximal response to 1S, 3R-ACPD (by ～40% at 300 μM L-AP3) without significantly affecting the concentration of 1S, 3R-ACPD required to cause half-maximal stimulation of the [~3H]-InsP_X response. 3 In contrast, at a higher concentration L-AP3 (1 mM) caused a large increase in [~3H]-InsP_X accumulation which was similar in magnitude in both the absence and presence of 1S, 3R-ACPD (300 μM). D-AP3 (1 mM) had no stimulatory effect alone and did not affect the response evoked by 1S, 3R-ACPD. L-AP3 (1 mM) also caused a large increase in Ins(1,4,5)P_3 accumulation. The magnitude of the response (4-5 fold increase over basal) approached that evoked by a maximally effective concentration of 1S, 3R-ACPD, but differed substantially in the time-course of the response. The stimulatory effects of 1S, 3R-ACPD and L-AP3 on Ins(1,4,5)P_3 accumulation were also similarly affected by decreases in extracellular calcium concentration.