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 Gβ₁ᵯE;₂ and a Nanoluciferase tagged free GβᵯE; sensor, MAS-GRK3-ct-NLuc with 14 specific G⍺ 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/11family, and generally thought to also couple to the PTX-sensitive G_i/o family; some reports have suggested G_scoupling 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 G₁₄. None activated any G_s protein. Interestingly, coupling was seen with the group I and II, but not the group III mGluRs to G₁₆. Slow but significant coupling to G_z was also seen with the group II receptors.