TY - JOUR T1 - 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. JF - Molecular Pharmacology JO - Mol Pharmacol SP - 586 LP - 594 VL - 49 IS - 4 AU - M Pizzi AU - P Galli AU - O Consolandi AU - V Arrighi AU - M Memo AU - P F Spano Y1 - 1996/04/01 UR - http://molpharm.aspetjournals.org/content/49/4/586.abstract N2 - We investigated the functional role of metabotropic glutamate receptors (mGluRs) in modulating glutamate-affected neuronal intracellular calcium concentration ([Ca2+]i) and cell viability in rat cerebellar granule cells. The mGluR agonist trans-1-amino-cyclopentane-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 (+)-alpha-methyl-4-carboxyphenylglycine blocked the effects of tACPD but intrinsically, they magnified the glutamate-mediated [Ca2+]i elevation. The tACPD-mediated decrease in [Ca2+]i rise occurred under experimental conditions superimposable on those producing neuroprotection in glutamate-exposed cultures. tACPD affected neither [Ca2+]i elevation due to KCI 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+]i 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 4beta-phorbol-12,13-dibutyrate reproduced mGluR-mediated inhibition of both glutamate-induced [Ca2+]i rise and neurotoxicity. In summary, these data suggest that activation of mGluR1-5 subtypes reduce glutamate-mediated (Ca2+]i rise through a mechanism involving protein kinase C activation. Such an effect results in neuroprotection. ER -