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.
Department of Physiology, University of Nottingham Medical School, Queen's Medical Centre, UK.
J
J
Cartmell
A R
AR
Curtis
J A
JA
Kemp
D A
DA
Kendall
S P
SP
Alexander
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D010716:Phosphatidylinositols / Q000378:metabolism; D017459:Receptors, Amino Acid / Q000378:metabolism*; D011983:Receptors, Purinergic / Q000502:physiology; D013237:Stereoisomerism
D005971:Glutamates; D010716:Phosphatidylinositols; D017459:Receptors, Amino Acid; D011983:Receptors, Purinergic; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D005576:Colforsin; D019830:Adenosine-5'-(N-ethylcarboxamide); D000242:Cyclic AMP; D000241:Adenosine