Extreme C terminus of G protein α-subunits contains a site that discriminates between Gi-coupled metabotropic glutamate receptors

Metabotropic glutamate receptors (mGlu receptors), the Ca2+-sensing receptor, gamma-aminobutyric acid type B receptors, and one group of pheromone receptors constitute a unique family (also called family 3) of heptahelical receptors, This original family shares no sequence similarity with any other G protein coupled receptors, The identification and comparison of the molecular determinants of receptor/G protein coupling within the different receptor families may help identify general rules involved in this protein/protein interaction. In order to detect possible contact sites important for coupling selectivity between family 3 receptors and the G protein alpha-subunits, we examined the coupling of the cyclase-inhibiting mGlu2 and mGlu4 receptors to chimeric alpha(q)-subunits bearing the 5 extreme C-terminal amino acid residues of either G alpha(qi)(,) G alpha(qo) or G alpha(qz). Whereas mGlu4 receptor activated all three chimeric G proteins, mGlu2 receptor activated G alpha(qi) and G alpha(qo) but not G alpha(qz). The mutation of isoleucine -4 of G alpha(qo) into cysteine was sufficient to recover coupling of the mutant G protein to mGlu2 receptor. Moreover, the mutation of cysteine -4 of G alpha(qo) into isoleucine was sufficient to suppress the coupling to mGlu2 receptor, Mutations at positions -5 and -1 had an effect on coupling efficiency, but not selectivity. Our results emphasize the importance of the residue -4 of the alpha-subunits in their specific interaction to heptahelical receptors by extending this finding on the third family of G protein coupled receptors.