Signaling specificity and kinetics of the human metabotropic glutamate receptors.

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 Gβγ sensor, MAS-GRK3-ct-NLuc with 14 specific Ga proteins heterologously expressed, representing each family. Canonically, the group II and III mGluRs (2&3, and 4, 6, 7&8, respectively) are thought to couple to G(i/o) exclusively. In addition, the group I mGluRs (1&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&5 through G(q/11), and perhaps surprisingly, not G(14). None activated any Gs 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.