Inhibition of Cyclic AMP Formation by a Selective Metabotropic Glutamate Receptor Agonist

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Abstract
It is well documented that the effects of excitatory ammo acid (EAA) agonists on phosphoinositide hydrolysis involve a GTP-binding protein-linked or “metabotropic’ receptor mechanism. The mechanisms by which EAAs alter cyclic AMP levels in brain slices, however, are not yet clear. In this study, the selective metabotropic EAA agonist trans-(±)-l-aminocyclopentane-l,3-dicarboxylic acid and its isomers were examined for effects on basal and forskolin-stimulated cyclic AMP formation in slices of the rat hippocampus. Trans-(±)-l-Aminocyclopentane-l,3-dicarboxylic acid had little effect on basal cyclic AMP but inhibited forskolin-stimulated cyclic AMP formation in a biphasic manner. The 1S,3R isomer of 1-aminocy-clopentane-l,3-dicarboxylic acid produced potent but only partial (~50%) inhibition of forskolin-stimulated cyclic AMP formation. 1R,3S–l-Aminocyclopentane-l,3-dicarboxylic acid fully inhibited forskolin-stimulated cyclic AMP but with lower potency than the IS,3R isomer. These results show that in addition to the formation of phosphoinositide-derived second messengers, the cellular consequences of selectively activating hippocampal metabotropic EAA receptors include an alteration of cellular cyclic AMP levels.