4-aminopyrrolidine-2-4-dicarboxylic-acid and 4-hydroxyphenylglycine

Metabotropic glutamate receptors (mGluRs) are widely distributed in mammalian brain, and are classified into three groups (Group I-III) according to mode of action: by I) homology of amino acid sequence, II) ligand selectivity, and III) signal transduction pathway. The mGluR-mediated signaling cascade is mainly investigated with the use of receptor-expressed non-neuronal cells; and thus, signaling mechanism in the central nervous systems remains to be elucidated. The aim of this study was to elucidate the manner of mGluR-G protein coupling in rat brain by measuring the activities of the high-affinity, low-KM GTPases in G alpha proteins. The selective Group II mGluR agonists, i.e., 2-(2,3-dicarboxycyclopropyl)glycine and (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate, elevated GTP hydrolysis in a concentration-dependent and saturable manner. On the other hand, the activation of high-affinity GTPase by the selective Group I mGluR agonist, (S)-3-hydroxyphenylglycine, or the selective Group III agonist, L-2-amino-4-phosphonobutylate, was hardly detected. These results indicated that the fashion of mGluR-G protein coupling varies among the mGluR subgroups. It is also suggested that high-affinity GTPase assay is useful for the investigation of mGluR-mediated signal transduction in the brain.

Topics: Animals; Cerebral Cortex; Cyclopropanes; Glycine; GTP Phosphohydrolases; GTP-Binding Proteins; Male; Proline; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Signal Transduction