Cloning and characterization of alternative mRNA forms for the rat metabotropic glutamate receptors mGluR7 and mGluR8

Novel mRNA isoforms for two members of the group III metabotropic glutamate receptors (mGluRs), called mGluR7b and mGluR8b, were identified from rat b rain cerebral cortex and hippocampus. In both cases, the alternative splici ng is generated by a similar out-of-frame insertion in the carboxyl-terminu s that results in the replacement of the last 16 amino acids of mGluR7 and mGluR8 by 23 and 16 different amino acids, respectively. Distribution analy sis for mGluR7 and mGluR8 isoforms revealed that the two splice variants ar e generally coexpressed in the same brain areas. The few exceptions were th e olfactory bulb, in which only the mGluR7a form could be detected by rever se transcription-polymerase chain reaction, and the lateral reticular and a mbiguus nuclei, which showed only mGluR8a labelling. Despite expression in the same regions, different mRNA abundance for the two variants of each rec eptor were observed. When transiently coexpressed in HEK 293 cells with the phospholipase C-activating chimeric G alpha qi9-G-protein, the a and b for ms for both receptor subtypes showed a similar pharmacological profile. The rank order of potencies for both was: DL-amino-4-phosphonobutyrate > L-ser ine-O-phosphate > glutamate. However, the agonist potencies were significan tly higher for mGluR8a, b compared with mGluR7a,b. In Xenopus oocytes, glut amate evoked currents only with mGluR8 when coexpressed with Kir 3.1 and 3. 4. Glutamate-induced currents were antagonized by the group II/III antagoni st (RS)-alpha-cyclopropyl-4-phosphonophenylglycine. In conclusion, the two isoforms of each receptor have identical pharmacological profiles when expr essed in heterologous systems, despite structural differences in the carbox yl-terminal domains.