RT Journal Article
SR Electronic
T1 Both enantiomers of 1-aminocyclopentyl-1,3-dicarboxylate are full agonists of metabotropic glutamate receptors coupled to phospholipase C.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 322
OP 327
VO 42
IS 2
A1 O Manzoni
A1 L Prezeau
A1 F A Rassendren
A1 F Sladeczek
A1 K Curry
A1 J Bockaert
YR 1992
UL http://molpharm.aspetjournals.org/content/42/2/322.abstract
AB We tested the effects of two enantiomers of a glutamate analogue, (trans)-1-aminocyclopentyl-1,3-dicarboxylate (t-ACPD), in striatal and cerebellar neurons in primary culture, as well as in Xenopus oocytes injected with cerebellar rat RNA. In the presence of MK-801, to avoid N-methyl-D-aspartate receptor activation, and 3 microM tetrodotoxin, both enantiomers [(1R,3S)- and (1S,3R)-t-ACPD] stimulated inositol phosphate (InsP) formation both in striatal neurons after 9-11 days in vitro [EC50, 3.7 +/- 1.1 microM, three experiments, and 33 +/- 7.5 microM, three experiments; maximal stimulatory effects, 252 +/- 15%, 13 experiments, and 269 +/- 15% of basal InsP formation, 14 experiments, for (1R,3S)- and (1S,3R)-t-ACPD, respectively] and in cerebellar granule cells after 9-11 days in vitro [EC50, 50 +/- 18 microM, four experiments, and 307 +/- 92 microM, four experiments; maximal stimulatory effects, 401 +/- 71%, eight experiments, and 423 +/- 75% of basal InsP formation, eight experiments, for (1R,3S)- and (1S,3R)-t-ACPD, respectively]. These effects were not additive, indicating that both enantiomers acted at the same receptor molecule. When we monitored t-ACPD-induced increases in intracellular Ca2+ concentration ([Ca2+]i) with fura-2 ratio-imaging, we found that both enantiomers could elicit similar increase in [Ca2+]i, in the presence of 1 microM MK-801 and 3 microM tetrodotoxin; these effects were also observed in the absence of external Ca2+. Moreover, in Xenopus oocytes injected with adult rat cerebellar RNA, both drugs elicited oscillatory increases of a Ca(2+)-dependent chloride conductance, with similar efficacy, with (1R,3S)-t-ACPD being the more potent isomer. These data are in contradiction to previous reports showing that, in "immature" cerebellar neurons and adult hippocampal slices, (1S,3R)-t-ACPD was either the only active enantiomer or a full agonist of metabotropic receptors, with (1R,3S)-t-ACPD being ineffective or a partial agonist. However, performing these experiments in immature (2-3 days in vitro) striatal or cerebellar neurons, we found that only (1S,3R)-t-ACPD was active in stimulating [Ca2+]i.