Functional Interaction between mGluR1 and 5

Metabotropic glutamate receptors (mGluRs), class C G‐protein‐coupled receptors, exist and function as dimers. Until recently, mGluRs were thought to mainly form homodimers, but recent evidence is showing that some, including the group I mGluRs (1 and 5), can physically interact. To date, the nature of this interaction has not been addressed, nor have the pharmacological and functional consequences. These questions were addressed by expressing mGluR1 and/or 5 in isolated sympathetic neurons from the rat superior cervical ganglion (SCG), and using modulation of the native calcium currents as an assay for receptor function. Our data suggest that mGluR1 and 5 show a functional interaction we have termed ‘trans‐activation,’ in which ligand binding in one receptor induces G protein activation in the other. Among the data supporting this model is the finding that co‐application of mGluR1‐selective competitive and noncompetitive antagonists prevent signaling in cells expressing both mGluR1 and 5. In these cells, combining allosteric and orthosteric mGluR1 antagonists – BAY 36–7620 (“BAY”) and 3‐MATIDA, completely occluded signaling, while either drug alone only partially blocked the response. These data suggest that while mGluR5 is expressed, it requires mGluR1 (uninhibited by BAY) to signal. These data support the hypothesis that mGluR1 and 5 signal in a mutually dependent manner.