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

The adenosine A2A receptor (A2AR), 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 A2AR in the inactive and active states. Our findings provide molecular-level insights into the permissive role of A2AR in mGlu5R activation, demonstrating that the inactive A2AR interface within the oligomer blocks the mGlu5R transmembrane helix 6 (TM6), which is crucial for activation. Upon A2AR 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:A2AR-TM4 interface in facilitating mGlu5R activation. These results highlight the intricate architecture of the mGlu5R:A2AR oligomer, advancing our understanding of GPCR oligomerization and its regulatory mechanisms on receptor activity.