Subtypes of metabotropic excitatory amino acid receptor distinguished by stereoisomers of the rigid glutamate analogue, 1-aminocyclopentane-1,3-dicar☐ylate

Abstract

The1 R,3 R- and1 R,3 S-isomers of 1-aminocyclopentane-1,3-dicar☐ylate (ACPD) failed to stimulate phosphoinositide turnover or modify A 2b adenosine receptor-stimulated cyclic AMP accumulation in guinea-pig cerebral cortical slices. In contrast, both1 S,3 R- and1 S,3 S-ACPD elicited concentration-dependent stimulations of phosphoinositide turnover (EC 50 values 35 and 97 μM, respectively) and potentiated A 2b-stimulated cAMP formation (17 and 58 μM, 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 (IC 50 values):1 S,3 S- (0.9 μM) > 1S,3 R- (2.1 μM> 1 R,3 R- (237 μM) > 1 R,3 S-ACPD (∼ 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 A 2b receptor-stimulated cAMP formation) and the inhibition of forskolin-stimulated cAMP accumulation. Furthermore, our results indicate the usefulness of 1 S,3 S-ACPD as a tool to selectively activate one of these subtypes.