GPCR oligomerization across classes: A2AR-mediated regulation of mGlu5R activation

The adenosine A_2A receptor (A_2AR), a class A GPCR, is a known player in neurological diseases, including Parkinson's disease and Alzheimer's disease, and is also implicated in SARS-CoV-2 infection. Recent studies have revealed its oligomerization with metabotropic glutamate receptor type 5 (mGlu₅R), a class C G protein coupled receptor (GPCR) that exists in the homodimeric form. Simultaneous activation of both receptors synergistically enhances mGlu₅R-mediated effects in the hippocampus. Despite their importance, the molecular mechanisms governing these interactions remain unclear. In this study, we used molecular modelling techniques, including molecular docking, extensive molecular dynamics (MD) simulations, and detailed analysis, to elucidate the interactions between mGlu₅R and A_2AR in the inactive and active states. Our findings provide molecular-level insights into the permissive role of A_2AR in mGlu₅R activation, demonstrating that the inactive A_2AR interface within the oligomer blocks the mGlu₅R transmembrane helix 6 (TM6), which is crucial for activation. Upon A_2AR activation, the oligomer interface undergoes conformational rearrangement, exposing mGlu₅R-TM6 and allowing for mGlu₅R activation. Furthermore, we identified a pivotal role of the mGlu₅R-TM4:A_2AR-TM4 interface in facilitating mGlu₅R activation. These results highlight the intricate architecture of the mGlu₅R:A_2AR oligomer, advancing our understanding of GPCR oligomerization and its regulatory mechanisms on receptor activity.