Subtypes of metabotropic excitatory amino acid receptor distinguished by stereoisomers of the rigid glutamate analogue, 1-aminocyclopentane-1,3-dicarboxylate.

The 1R,3R- and 1R,3S-isomers of 1-aminocyclopentane-1,3-dicarboxylate (ACPD) failed to stimulate phosphoinositide turnover or modify A2b adenosine receptor-stimulated cyclic AMP accumulation in guinea-pig cerebral cortical slices. In contrast, both 1S,3R- and 1S,3S-ACPD elicited concentration-dependent stimulations of phosphoinositide turnover (EC50 values 35 and 97 microM, respectively) and potentiated A2b-stimulated cAMP formation (17 and 58 microM, respectively). When forskolin was used to elevate cyclic AMP levels, however, all four isomers elicited concentration-dependent inhibitions of cyclic AMP formation to the same extent (approximately 90% inhibition). For this response the rank order of potencies were (IC50 values): 1S,3S-(0.9 microM) > 1S,3R-(2.1 microM) > 1R,3R-(237 microM) > 1R,3S-ACPD (approximately 1 mM). These data suggest the presence in guinea-pig cerebral cortex of two distinct subtypes of ACPD receptor coupled to phosphoinositide hydrolysis (and the potentiation of A2b receptor-stimulated cAMP formation) and the inhibition of forskolin-stimulated cAMP accumulation. Furthermore, our results indicate the usefulness of 1S,3S-ACPD as a tool to selectively activate one of these subtypes.