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 bioluminescence resonance energy transfer-based assay that detects the interaction between a split YFP-tagged Gβ ₁γ₂ and a Nanoluciferase tagged free Gβγ sensor, MAS-GRK3-ct- nanoluciferase with 14 specific Gα proteins heterologously expressed, representing each family. Canonically, the group II and III mGluRs (2 and 3 and 4, 6, 7, and 8, respectively) are thought to couple to G_i/o exclusively. In addition, the group I mGluRs (1 and 5) are known to couple to the G_q/11 family and generally thought to also couple to the pertussis toxin-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 eight mGluRs through the G_i/o proteins and only mGluR1 and mGluR5 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. SIGNIFICANCE STATEMENT: Metabotropic glutamate receptor (mGluR)-G protein coupling has not been thoroughly examined, and some controversy remains about whether some mGluRs can activate G_αs family members. Here we examine the ability of each mGluR to activate representative members of every G_α protein family. While all mGluRs can activate G_αi/o proteins, only the group I mGluRs couple to G_αq/11, and no members of the family can activate G_αs family members, including the group I receptors alone or with positive allosteric modulators.