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Inhibition of the Phospholipase C‐Linked Metabotropic Glutamate Receptor by 2‐Amino‐3‐Phosphonopropionate Is Dependent on Extracellular Calcium
Author(s) -
Lonart Gyorgy,
Alagarsamy Sudarkodi,
Ravula Radhika,
Wang Jia,
Johnson Kenneth M.
Publication year - 1992
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 - 10.1111/j.1471-4159.1992.tb09438.x
Subject(s) - acpd , metabotropic glutamate receptor , metabotropic receptor , extracellular , glutamate receptor , agonist , biophysics , chemistry , biochemistry , biology , receptor , medicine
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,3 R ‐ACPD), a selective agonist of this receptor. The response produced by maximally effective concentrations of l ‐AP‐3 and 1S,3 R ‐ACPD together for 5 min was not significantly different from that produced by 1S,3 R ‐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,3 R ‐ACPD. This inhibition was long‐lasting (wash‐resistant) and was reversed by reduction of the extracellular Ca 2+ concentration. Also, pretreatment for 40 min with 1S,3 R ‐ACPD reduced, but did not completely block, the response to readdition of 1S,3 R ‐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 Ca 2+ . The possible roles of receptor occupancy and inhibition of glutamate uptake by AP‐3 are also discussed.