Abstract Metabotropic glutamate receptors (mGluRs) are obligate dimer G protein coupled receptors that can all function as homodimers. Here, each mGluR homodimer was examined for its G protein coupling profile using a BRET based assay that detects the interaction between a split YFP-tagged Gβ 1 γ 2 and a Nanoluc tagged free Gβ γ sensor, MAS-GRK3-ct-NLuc with 14 specific G⍺ proteins heterologously expressed, representing each family. Canonically, the group II and III mGluRs (2&amp;3, and 4, 6, 7&amp;8, respectively) are thought to couple to G i/o exclusively. In addition, the group I mGluRs (1&amp;5) are known to couple to the G q/11 family, and generally thought to also couple to the PTX-sensitive G i/o family; some reports have suggested G s coupling is possible as cAMP elevations have been noted. In this study, coupling was observed with all 8 mGluRs through the G i/o proteins, and only mGluR1&amp;5 through G q/11 , and perhaps surprisingly, not G 14 . None activated any G s protein. Interestingly, coupling was seen with the group I and II, but not the group III mGluRs to G 16 . Slow but significant coupling to G z was also seen with the group II receptors.

Signaling specificity and kinetics of the human metabotropic glutamate receptors