CLONING AND EXPRESSION OF RAT METABOTROPIC GLUTAMATE-RECEPTOR-8 REVEALS A DISTINCT PHARMACOLOGICAL PROFILE

The metabotropic glutamate receptor (mGluR) cDNAs were originally clon ed from rat, except for the mouse cDNA clone encoding mGluR8. Mouse mG luR8 couples weakly to the inhibition of adenylate cyclase, thus hinde ring the characterization of its pharmacological properties. We isolat ed a rat mGluR8 cDNA that encodes a protein of 908 amino acids. In sit u hybridization revealed prominent mGluR8 mRNA expression in olfactory bulb, pontine gray, lateral reticular nucleus of the thalamus, and pi riform cortex. Less abundant expression was detected in cerebral corte x, hippocampus, cerebellum, and mammillary body. Glutamate evoked pert ussis toxin-sensitive potassium currents in Xenopus laevis oocytes coe xpressing mGluR8 and G protein-coupled inwardly rectifying potassium c hannels. mGluR8 was also activated by the group III-specific agonist L -2-amino-4-phosphonobutyric acid; (2(S),1'(S),2'(S)]-2-(carboxycyclopr opyI)glycine, which has been frequently used as a selective group II a gonist; and the nonselective agonist (1(S),3(R)]-1-aminocyclopentane-1 ,3-dicarboxylic acid but not by the group I-specific agonist 3,5-dihyd roxyphenylglycine or the group II-specific agonist ),2'(R),3(R)]-2-(2, 3-dicarboxycyclopropyl)glycine. The agonist profile in order of potenc y was [2(S),1'(S),2'(S)]-2-(carboxycyclopropyl)glycin approximate to L -2-amino-4-phosphonobutyric acid > glutamate much greater than [1(S),3 (R)]-1-aminocyclopentane-1,3-dicarboxylic acid, with EC(50) values of 0.63, 0.67, 2.5, and 47 mu M, respectively. Both the group I/II-specif ic antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine and the group III-specific antagonist alpha-methyl-amino-phosphonobutyrate inhibited mGluR8. The pharmacological profile of mGluR8 is distinct among mGluR s but closely matches that of presynaptic inhibition in some central n ervous system pathways. Thus, cellular responses mediated by both grou p II and III agonists may in some cases reflect activation of mGluR8 r ather than multiple mGluR subtypes.