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

The stimulation of high-affinity GTPase activity through metabotropic glutamate 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 other 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-IV) 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)-4C3HPG] is approximately equal to 1S,3R-1-aminocyclopentane-1,3-dicarboxylate [(1S,3R)-ACPD] > (S)-3-carboxy-4-hydroxyphenylglycine [(S)-3C4HPG] is approximately equal to ibotenate. The negative logarithmically transformed EC50 (pEC(50)) values of these compounds in both brain regions were significantly correlated with those reported previously in the cerebral cortical membranes (N. Nishi et al., Br. J. Pharmacol., 130, 1664 - 1670, 2000). On the contrary, 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-phosphate (L-SOP) had little or no effects even at the highest concentration examined. Quisqualate was also a very weak agonist in both regions. These results indicate that mGluR-mediated high-affinity GTPase activity derives from the Gi proteins associated with adenylyl cyclase inhibition through group II mGluRs, in particular the mGluR2 subtype, in rat hippocampal and striatal membranes.