Inhibition of the Phospholipase C‐Linked Metabotropic Glutamate Receptor by 2‐Amino‐3‐Phosphonopropionate Is Dependent on Extracellular Calcium

Abstract: D,L‐2‐Amino‐3‐phosphonopropionate (AP‐3), a proposed metabotropic receptor antagonist, produced a concentration‐dependent increase in the formation of inositol 1,4,5‐trisphosphate in rat hippocampal slices. The response was maximal at 1 mM and completely due to the l‐isomer. d,l‐AP‐3 was half as efficacious as (1S,3R)‐1‐aminocyclopentane‐1,3‐dicarboxylic acid (1S,3R‐ACPD), a selective agonist of this receptor. The response produced by maximally effective concentrations of l‐AP‐3 and 1S,3R‐ACPD together for 5 min was not significantly different from that produced by 1S,3R‐ACPD alone. However, pretreatment for 40 min with either 1 mM l‐AP‐3 or D,L‐AP‐3 completely inhibited the response to 1S,3R‐ACPD. This inhibition was long‐lasting (wash‐resistant) and was reversed by reduction of the extracellular Ca²⁺ concentration. Also, pretreatment for 40 min with 1S,3R‐ACPD reduced, but did not completely block, the response to readdition of 1S,3R‐ACPD. l‐AP‐3 (1 mM) also produced a stereoselective 2.3‐fold increase in the efflux of glutamate from the hippocampal slices. These data suggest that incubation of hippocampal slices with AP‐3 induces a time‐dependent desensitization of the metabotropic response by a mechanism that is dependent on extracellular Ca²⁺. The possible roles of receptor occupancy and inhibition of glutamate uptake by AP‐3 are also discussed.