Signaling specificity and kinetics of the human metabotropic glutamate receptors

Abstract

AbstractMetabotropic 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 Gβ1γ2and a Nanoluc tagged free Gβγsensor, 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 Gi/oexclusively. In addition, the group I mGluRs (1&5) are known to couple to the Gq/11family, and generally thought to also couple to the PTX-sensitive Gi/ofamily; some reports have suggested Gscoupling is possible as cAMP elevations have been noted. In this study, coupling was observed with all 8 mGluRs through the Gi/oproteins, and only mGluR1&5 through Gq/11, and perhaps surprisingly, not G14. None activated any Gsprotein. Interestingly, coupling was seen with the group I and II, but not the group III mGluRs to G16. Slow but significant coupling to Gzwas also seen with the group II receptors.