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.
|Number of pages||9|
|Publication status||Published - Apr 1996|
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