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

The adenosine A receptor (AR), 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 (mGluR), a class C G protein coupled receptor (GPCR) that exists in the homodimeric form. Simultaneous activation of both receptors synergistically enhances mGluR-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 mGluR and AR in the inactive and active states. Our findings provide molecular-level insights into the permissive role of AR in mGluR activation, demonstrating that the inactive AR interface within the oligomer blocks the mGluR transmembrane helix 6 (TM6), which is crucial for activation. Upon AR activation, the oligomer interface undergoes conformational rearrangement, exposing mGluR-TM6 and allowing for mGluR activation. Furthermore, we identified a pivotal role of the mGluR-TM4:AR-TM4 interface in facilitating mGluR activation. These results highlight the intricate architecture of the mGluR:AR oligomer, advancing our understanding of GPCR oligomerization and its regulatory mechanisms on receptor activity.