Molecular pharmacology of mGlu7/8 heterodimers reveals unique properties of orthosteric agonists and positive allosteric modulators.

The metabotropic glutamate (mGlu) receptors are family C G protein-coupled receptors that are widely expressed throughout the central nervous system and function as either homodimers or heterodimers. Recent literature suggests that specific mGlu heterodimer subtypes play critical functional roles in the brain and show unique pharmacological signatures relative to homodimers. We have previously shown that mGlu7/8 heterodimers may modulate the induction of hippocampal synaptic plasticity using negative allosteric modulators that differentiate between mGlu7/7 homodimers and mGlu7/8 heterodimers in vitro. However, we have yet to characterize positive allosteric modulators (PAMs) targeting mGlu7 and mGlu8 in a heterodimer-specific assay. Here, we investigated the molecular pharmacology of mGlu7/8 heterodimers relative to mGlu7/7 and mGlu8/8 homodimers using PAMs and various orthosteric agonists using functional assays of controlled receptor activity in HEK293 cells. We demonstrate that an mGlu8-selective agonist is only active at mGlu8/8 homodimers and acts as an antagonist at mGlu7/8 heterodimers. In addition, we show that specific PAMs, such as VU0155094, show greater efficacy at mGlu7/8 heterodimers in specific assays. Overall, these findings have important implications for the physiological and behavioral roles of mGlu heterodimers and homodimers as it relates to the pharmacology of these compounds. In addition, this study provides a rationale for using a pharmacological toolkit to selectively probe mGlu7/7, mGlu8/8, and mGlu7/8 dimers in native tissues. SIGNIFICANCE STATEMENT: Pharmacological profiling of ligands at mGlu7/8 heterodimers reveals that this receptor exhibits a unique pharmacological signature relative to mGlu7/7 and mGlu8/8 homodimers. This study provides an incentive to investigate the pharmacology of other mGlu heterodimers, screen for heterodimer selective compounds, and use pharmacological tools to investigate the physiological effects of mGlu7/8 dimers in native tissues.