Jpn. J. Pharmacol. 84 (4), 399-404 (2000)

Stimulation of High-Affinity GTPase Activity Through Group II Metabotropic Glutamate Receptors in Rat Hippocampal and Striatal Membranes

Yuji Odagaki*, Nobuyuki Nishi and Tsukasa Koyama

Department of Psychiatry, Hokkaido University Graduate School of Medicine, North 15, West 7, Sapporo 060-8638, Japan
*Corresponding author.
Present address for correspondence: Department of Psychiatry, Saitama Medical School, 38 Morohongo, Moroyama-cho Iruma-gun, Saitama 350-0495, Japan
FAX:+81-492-76-1622, E-mail: odagaki@saitama-med.ac.jp

Abstract: 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)&nbspÊá=áÊÊ(2S,1¢S,2¢S)-2-(carboxycyclopropyl)glycine (L-CCG-I)ÊÊ>ÊL-glutamate&nbspÊá=áÊÊ2R,4R-4-aminopyrrolidine-2,4-dicarboxylate [(2R,4R)-APDC]ÊÊ>Ê(S)-4-carboxy-3-hydroxyphenylglycine [(S)-4C3HPG]&nbspÊá=áÊÊ1S,3R-1-aminocyclopentane-1,3-dicarboxylate [(1S,3R)-ACPD]ÊÊ>Ê(S)-3-carboxy-4-hydroxyphenylglycine [(S)-3C4HPG]&nbspÊá=áÊÊibotenate. The negative logarithmically transformed EC₅₀ (pEC₅₀) values of these compounds in both brain regions were significantly correlated with those reported previously in the cerebral cortical membranes (N.ÊNishiÊetÊal., Br. J. Pharmacol., 130, 1664-1670, 2000). On the contrary, other reagents including a selective groupÊI mGluRs agonist, (RS)-3,5-dihydroxyphenylglycine [(RS)-3,5-DHPG], and selective groupÊIII 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 G_i proteins associated with adenylyl cyclase inhibition through groupÊII mGluRs, in particular the mGluR2 subtype, in rat hippocampal and striatal membranes.

Keywords: Metabotropic glutamate receptor, GÊprotein, High-affinity GTPase, Hippocampus, Striatum