Metabotropic and ionotropic transducers of glutamate signal inversely control cytoplasmic Ca2+ concentration and excitotoxicity in cultured cerebellar granule cells: Pivotal role of protein kinase C

M. Pizzi, P. Galli, O. Consolandi, V. Arrighi, M. Memo, P. F. Spano

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Abstract

We investigated the functional role of metabotropic glutamate receptors (mGluRs) in modulating glutamate-affected neuronal intracellular calcium concentration ([Ca2+]) and cell viability in rat cerebellar granule cells. The mGluR agonist trans-1-aminocyclopentane-1,3-dicarboxylic acid (tACPD) induced a transient increase in [Ca2+]i, which seemed to be developmentally regulated and maximal at 4 days in vitro. In addition, tACPD significantly prevented the [Ca2+]i rise produced by glutamate or by N-methyl-D-aspartate. The mGluR antagonists L-2-amino-3-phosphonopropionic and (+)-α-methyl-4-carboxyphenylglycine blocked the effects of tACPD, but intrinsically, they magnified the glutamate-mediated [Ca2+], elevation. The tACPD-mediated decrease in [Ca2+], rise occurred under experimental conditions superimposable on those producing neuroprotection in glutamate-exposed cultures. tACPD affected neither [Ca2+], elevation due to KCl nor that evoked by the calcium ionophore A 23187. The inhibitory effect of tACPD was also unaffected by K+ channel blockade produced by tetraethylammonium. The tACPD effects were fully mimicked by quisqualate and (RS)-3,5-dihydroxyphenylglycine, whereas they were only partially reproduced by (2S,1′S,2′S)-2-carboxycyclopropyl-glycine. L-2-Amino-4-phosphonobutyrate was inactive in preventing glutamate-mediated [Ca2+], rise and neurotoxicity. The tACPD inhibitory responses seemed to be highly sensitive to protein kinase C blockade by bisindolylmaleimide or staurosporine, whereas they were weakly affected by the cAMP analogue dibutyryl cAMP. The protein kinase C activator 4β-phorbol-12,13-dibutyrate reproduced mGluR-mediated inhibition of both glutamate-induced [Ca2+], rise and neurotoxicity. In summary, these data suggest that activation of mGluR1-5 subtypes reduce glutamate-mediated [Ca2+], rise through a mechanism involving protein kinase C activation. Such an effect results in neuroprotection.

Original languageEnglish
Pages (from-to)586-594
Number of pages9
JournalMolecular Pharmacology
Volume49
Issue number4
Publication statusPublished - Apr 1996

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Transducers
Protein Kinase C
Glutamic Acid
Quisqualic Acid
Phorbol 12,13-Dibutyrate
Metabotropic Glutamate Receptors
Tetraethylammonium
Staurosporine
Calcium Ionophores
1-amino-1,3-dicarboxycyclopentane
Calcimycin
N-Methylaspartate
Cell Survival
Calcium

ASJC Scopus subject areas

  • Pharmacology

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Metabotropic and ionotropic transducers of glutamate signal inversely control cytoplasmic Ca2+ concentration and excitotoxicity in cultured cerebellar granule cells : Pivotal role of protein kinase C. / Pizzi, M.; Galli, P.; Consolandi, O.; Arrighi, V.; Memo, M.; Spano, P. F.

In: Molecular Pharmacology, Vol. 49, No. 4, 04.1996, p. 586-594.

Research output: Contribution to journalArticle

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AU - Consolandi, O.

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AU - Memo, M.

AU - Spano, P. F.

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