Presynaptic mGlu1 and mGlu5 autoreceptors facilitate glutamate exocytosis from mouse cortical nerve endings

Veronica Musante, Elisa Neri, Marco Feligioni, Aldamaria Puliti, Marco Pedrazzi, Valerio Conti, Cesare Usai, Alberto Diaspro, Roberto Ravazzolo, Jeremy M. Henley, Giuseppe Battaglia, Anna Pittaluga

Research output: Contribution to journalArticle

Abstract

The effects of mGlu1 and mGlu5 receptor activation on the depolarization-evoked release of [3H]d-aspartate ([3H]d-ASP) from mouse cortical synaptosomes were investigated. The mGlu1/5 receptor agonist 3,5-DHPG (0.1-100 μM) potentiated the K+(12 mM)-evoked [3H]d-ASP overflow. The potentiation occurred in a concentration-dependent manner showing a biphasic pattern. The agonist potentiated [3H]d-ASP exocytosis when applied at 0.3 μM; the efficacy of 3,5-DHPG then rapidly declined and reappeared at 30-100 μM. The fall of efficacy of agonist at intermediate concentration may be consistent with 3,5-DHPG-induced receptor desensitization. Facilitation of [3H]d-ASP exocytosis caused by 0.3 μM 3,5-DHPG was prevented by the selective mGlu5 receptor antagonist MPEP, but was insensitive to the selective mGlu1 receptor antagonist CPCCOEt. In contrast, CPCCOEt prevented the potentiation by 50 μM 3,5-DHPG, while MPEP had minimal effect. Unexpectedly, LY 367385 antagonized both the 3,5-DHPG-induced effects. A total of 0.3 μM 3,5-DHPG failed to facilitate the K+-evoked [3H]d-ASP overflow from mGlu5 receptor knockout (mGlu5-/-) cortical synaptosomes, but not from nerve terminals prepared from the cortex of animals lacking the mGlu1 receptors, the crv4/crv4 mice. On the contrary, 50 μM 3,5-DHPG failed to affect the [3H]d-ASP exocytosis from cortical synaptosomes obtained from crv4/crv4 and mGlu5-/-mice. Western blot analyses in subsynaptic fractions support the existence of both mGlu1 and mGlu5 autoreceptors located presynaptically, while immunocytochemistry revealed their presence at glutamatergic terminals. We propose that mGlu1 and mGlu5 autoreceptors exist on mouse glutamatergic cortical terminals; mGlu5 receptors may represent the "high affinity" binding sites for 3,5-DHPG, while mGlu1 autoreceptors represent the "low affinity" binding sites.

Original languageEnglish
Pages (from-to)474-482
Number of pages9
JournalNeuropharmacology
Volume55
Issue number4
DOIs
Publication statusPublished - Sep 2008

Keywords

  • [H]d-aspartate release
  • crv4 Mice
  • mGlu1 autoreceptor
  • mGlu5 autoreceptor
  • mGlu5 Receptor knockout mice
  • Mouse cortical synaptosomes

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

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  • Cite this

    Musante, V., Neri, E., Feligioni, M., Puliti, A., Pedrazzi, M., Conti, V., Usai, C., Diaspro, A., Ravazzolo, R., Henley, J. M., Battaglia, G., & Pittaluga, A. (2008). Presynaptic mGlu1 and mGlu5 autoreceptors facilitate glutamate exocytosis from mouse cortical nerve endings. Neuropharmacology, 55(4), 474-482. https://doi.org/10.1016/j.neuropharm.2008.06.056