Stimulation of high-affinity GTPase activity through group II metabotropicglutamate receptors in rat hippocampal and striatal membranes

The stimulation of high-affinity GTPase activity through metabotropic gluta mate receptors (mGluRs) was pharmacologically characterized with the use of a series of agonists for mGluRs in rat hippocampal and striatal membranes. The pharmacological profile of the response was almost identical to each o ther between both brain regions. Thus, the high-affinity GTPase activities were stimulated by several mGluR-related compounds with the following rank order of potency: (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-I V) is approximately equal to (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L- CCG-I) > L-glutamate is approximately equal to 2R,4R-4-aminopyrrolidine-2,4 -dicarboxylate [(2R,4R)-APDC]> (S)-4-carboxy-3-hydroxyphenylglycine [(S)-4C 3HPG] is approximately equal to 1S,3R-1-aminocyclopentane-1,3-dicarboxylate [(1S,3R)-ACPD] > (S)-3-carboxy-4-hydroxyphenylglycine [(S)-3C4HPG] is appr oximately equal to ibotenate. The negative logarithmically transformed EC50 (pEC(50)) values of these compounds in both brain regions were significant ly correlated with those reported previously in the cerebral cortical membr anes (N. Nishi et al., Br. J. Pharmacol., 130, 1664 - 1670, 2000). On the c ontrary, other reagents including a selective group I mGluRs agonist, (RS)- 3,5-dihydroxyphenylglycine [(RS)-3,5-DHPG], and selective group III mGluRs agonists such as L(+)-2-amino-4-phosphonobutylate (L-AP4) and L-serine-O-ph osphate (L-SOP) had little or no effects even at the highest concentration examined. Quisqualate was also a very weak agonist in both regions. These r esults indicate that mGluR-mediated high-affinity GTPase activity derives f rom the Gi proteins associated with adenylyl cyclase inhibition through gro up II mGluRs, in particular the mGluR2 subtype, in rat hippocampal and stri atal membranes.