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

Gyorgy Lonart, Sudarkodi Alagarsamy, Radhika Ravula, Jia Wang, Kenneth M. Johnson

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)772-775
Number of pages4
JournalJournal of neurochemistry
Volume59
Issue number2
DOIs
StatePublished - Aug 1992

Keywords

  • Desensitization
  • Hippocampus
  • Inositol 1,4,5‐trisphosphate
  • d,l‐2‐Amino‐3‐phosphonopropionate
  • trans‐D,L‐1‐Aminocyclopentane‐1,3‐dicarboxylic acid

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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