DOMAINS INVOLVED IN THE SPECIFICITY OF G-PROTEIN ACTIVATION IN PHOSPHOLIPASE C-COUPLED METABOTROPIC GLUTAMATE RECEPTORS

G protein-coupled glutamate receptors (mGluR) have recently been chara cterized. These receptors have seven putative transmembrane domains, b ut display no sequence homology with the large family of G protein-cou pled receptors. They constitute therefore a new family of receptors. W hereas mGluR1 and mGluR5 activate phospholipase C (PLC), mGluR2, mGluR 3, mGluR4 and mGluR6 inhibit adenylyl cyclase (AC) activity. The third putative intracellular loop, which determines the G protein specifici ty in many G protein-coupled receptors, is highly conserved among mGlu Rs, and may therefore not be involved in the specific recognition of G proteins in this receptor family. By constructing chimeric receptors between the AC-coupled mGluR3 and the PLC-coupled mGluR1c, we report h ere that both the C-terminal end of the second intracellular loop and the segment located downstream of the seventh transmembrane domain are necessary for the specific activation of PLC by mGluR1c. These two se gments are rich in basic residues and are likely to be amphipathic alp ha-helices, two characteristics of the G protein interacting domains o f all G protein-coupled receptors. This indicates that whereas no amin o acid sequence homology between mGluRs and the other G protein-couple d receptors can be found, their G protein interacting domains have sim ilar structural features.