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

NEUROPHARMACOLOGY

卷:55

Article

Musante, Veronica¹  Neri, Elisa¹  Feligioni, Marco²  Puliti, Aldamaria^3,4,5  Pedrazzi, Marco^5,6  Conti, Valerio^4,7  Usai, Cesare⁸  Diaspro, Alberto⁹  Ravazzolo, Roberto^3,4,5  Henley, Jeremy M.²  Battaglia, Giuseppe¹⁰  Pittaluga, Anna^1,3 

[1] Univ Genoa, Sect Pharmacol & Toxicol, Dept Expt Med, Genoa, Italy

[2] Univ Bristol, Sch Med Sci, Dept Anat, MRC Ctr Synapt Plastic, Bristol BS8 1TD, Avon, England

[3] Univ Genoa, Ctr Excellence Biomed Res, Genoa, Italy

[4] G Gaslini Inst Children, Lab Mol Genet & Cytogenet, Genoa, Italy

[5] Univ Genoa, Dept Pediat Sci, Genoa, Italy

[6] Univ Genoa, Biochem Sect, Dept Expt Med, Genoa, Italy

[7] G Gaslini Inst Children, Renal Child Fdn, Genoa, Italy

[8] CNR, Inst Biophys, Genoa, Italy

[9] Univ Genoa, Dept Phys, Genoa, Italy

[10] INM Neuromed, Pozzilli, IS, Italy

关键词: mouse cortical synaptosomes;    [H-3]D-aspartate release;    mGlu1 autoreceptor;    mGlu5 autoreceptor;    crv4 mice;    mGlu5 receptor knockout mice;   

DOI  :  10.1016/j.neuropharm.2008.06.056

来源: Elsevier

【 摘 要 】

The effects of mGlu1 and mGlu5 receptor activation on the depolarization-evoked release of [3 HID-aspartate ([3 HID-ASP) from mouse cortical synaptosomes were investigated. The mGlu1/5 receptor agonist 3,5-DHPG (0.1-100 mu M) potentiated the K+(12 mM)-evoked [H-3]D-ASP overflow. The potentiation occurred in a concentration-dependent manner showing a biphasic pattern. The agonist potentiated [H-3]D-ASP exocytosis when applied at 0.3 mu M; the efficacy of 3,5-DHPG then rapidly declined and reappeared at 30-100 mu M. The fall of efficacy of agonist at intermediate concentration may be consistent with 3,5-DHPG-induced receptor desensitization. Facilitation of [H-3]D-ASP exocytosis caused by 0.3 mu M 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 mu M 3,5-DHPG, while MPEP had minimal effect. Unexpectedly, LY 367385 antagonized both the 3,5-DHPG-induced effects. A total of 0.3 mu M 3,5-DHPG failed to facilitate the K+-evoked [H-3]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 mu M 3,5-DHPG failed to affect the 13 HID-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. (C) 2008 Elsevier Ltd. All rights reserved.

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