A pharmacological signature to selectively identify mGlu7-containing heterodimers

The eight metabotropic glutamate (mGlu1-8) receptors are key players in the modulation of the synaptic transmission. They have long been considered as homodimeric entities since they function only as mandatory dimers. However, it has been recently proposed that they can also heterodimerize in specific combinations, adding 16 new dimeric mGlu entities. This implied to characterize each heterodimer to develop tools to detect specifically their expression and activity in native tissues.The mGlu7 homodimers have a very low affinity for glutamate (mM) compared to that of the other mGlus (µM). It was already highlighted that mGlu7 subunit is able to heterodimerize with mGlu2. It was then crucial to determine the specific pharmacological properties of mGlu7/2, compared to mGlu7 and mGlu2 homodimers, in order to specifically identify mGlu7/2 in vivo.We then determined the pharmacological properties of mGlu2, mGlu7 and mGlu7/2, transiently expressed in HEK cells. For mGlu7/2, we used the optimized quality control system based on the GABAB receptor to make sure that only the heterodimer reached the cell surface. Orthosteric and allosteric ligands for mGlu2 and mGlu7 were tested on each homodimer and on mGlu7/2 heterodimer. We observed a symmetric activation of mGlu7/2 while coupling to the G proteins through mGlu7. We then identified a pharmacological signature of this heterodimer, using ligands that act differently on mGlu7 or mGlu2 subunits depending on whether they are part of a homo- or a heterodimeric entity. This pharmacological signature will be used to identify mGlu7/2 heterodimers in the brain.