Résumé
Specific domains of the G-protein α subunit have been shown to control coupling to heptahelical receptors. The extreme N and C termini and a region between α4 and α5 helices of the G-protein α subunit are known to determine selective interaction with the receptors. The metabotropic glutamate receptor 2 activated both mouse Gα15 and its human homologue Gα16, whereas metabotropic glutamate receptor 8 activated Gα15 only. The extreme C-terminal 20 amino acid residues are identical between the Gα15 and Gα16 and are therefore unlikely to be involved in coupling selectivity. Our data reveal two regions on Gα16 that inhibit its coupling to metabotropic glutamate receptor 8. On a three-dimensional model, both regions are found in a close proximity to the extreme C terminus of Gα16. One module comprises α4 helix, α4−β6 loop (L9 Loop), β6 sheet, and α5 helix. The other, not described previously, is located within the loop that links the N-terminal α helix to the β1 strand of the Ras-like domain of the α subunit. Coupling of Gα16 protein to the metabotropic glutamate receptor 8 is partially modulated by each module alone, whereas both modules are needed to eliminate the coupling fully.