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

19 Citations (Scopus)

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
StatePublished - Aug 1992

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Type C Phospholipases
Calcium
Glutamic Acid
Inositol 1,4,5-Trisphosphate
Transcription Factor AP-1
Isomers
metabotropic glutamate receptor 2
1-amino-1,3-dicarboxycyclopentane
2-amino-3-phosphonopropionic acid
Rats

Keywords

  • D,L-2-Amino-3-phosphonopropionate
  • Desensitization
  • Hippocampus
  • Inositol 1,4,5-trisphosphate
  • Trans-D,L-1-Aminocyclopentane-1,3-dicarboxylic acid

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Inhibition of the phospholipase C-linked metabotropic glutamate receptor by 2-amino-3-phosphonopropionate is dependent on extracellular calcium. / Lonart, Gyorgy; Alagarsamy, Sudarkodi; Ravula, Radhika; Wang, Jia; Johnson, Kenneth M.

In: Journal of Neurochemistry, Vol. 59, No. 2, 08.1992, p. 772-775.

Research output: Contribution to journalArticle

Lonart, Gyorgy ; Alagarsamy, Sudarkodi ; Ravula, Radhika ; Wang, Jia ; Johnson, Kenneth M. / Inhibition of the phospholipase C-linked metabotropic glutamate receptor by 2-amino-3-phosphonopropionate is dependent on extracellular calcium. In: Journal of Neurochemistry. 1992 ; Vol. 59, No. 2. pp. 772-775.
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AU - Wang, Jia

AU - Johnson, Kenneth M.

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AB - 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.

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