Résumé
Together with the calcium-sensing receptor, the metabotropic glutamate receptors (mGluRs) share no sequence homology with the other G protein-coupled receptors (GPCRs) and therefore constitute a new family of receptors. Recently, it was reported that G(alpha 15) and G(alpha 16) subunits allow many GPCRs to activate phospholipase C (PLC). Furthermore, the exchange of a few carboxyl-terminal residues of G(alpha q) by those of G(alpha i2) of G(alpha o) allows the resulting chimeric G(alpha) subunits (G(alpha qi) and G(alpha qo), respectively) to couple G(i)-coupled receptors to PLC. We report that mGluR2 and mGluR4, two receptors negatively coupled to adenylyl cyclase, activate PLC when coexpressed with G(alpha 15), G(alpha qi), or G(alpha qo). This indicates that the carboxyl-terminal end of the G(alpha) subunit also plays an important role in the specific interaction between mGluRs and the G proteins. In addition, the measurement of PLC activation by G(i)-coupled mGluRs coexpressed with these G(alpha>) subunits constitutes an easy functional assay for the pharmacological characterization of these receptors, The rank order of potency of antagonists was found to be (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine approximate to (R,S)-alpha-methyl-4-phosphonophenylglycine > (R,S)-alpha-methyl-4-sulfonophenylglycine > (R,S)-alpha-methyl-4-tetrazolylphenylglycine = (S)-2-amino-2-methyl-4-phosphonobutyrate for mGluR2 and to be (R,S)-alpha-methyl-4-phosphonophenylglycine greater than or equal to (S)-2-amino-2-methyl-4-phosphonobutyrate >> (R,S)-alpha-methyl-4-sulfonophenylglycine [(R,S)-alpha-methyl-4-tetrazolylphenylglycine and (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine being inactive at 1 mM] for mGluR4. Using this functional assay, (R,S)-alpha-methyl-4-phosphonophenylglycine was found to have a similar K-B value for mGluR2 and mGluR4.