Abstract
The lipid composition of the plasma membrane is a key parameter in controlling signal transduction through G protein-coupled receptors (GPCRs). Adenosine A2A receptor (A2AAR) is located in the lipid bilayers of cells, containing acyl chains derived from docosahexaenoic acid (DHA). For the NMR studies, we prepared A2AAR in lipid bilayers of nanodiscs, containing DHA chains and other acyl chains. The DHA chains in nanodiscs enhanced the activation of G proteins by A2AAR. Our NMR studies revealed that the DHA chains redistribute the multiple conformations of A2AAR toward those preferable for G protein binding. In these conformations, the rotational angle of transmembrane helix 6 is similar to that in the A2AAR-G protein complex, suggesting that the population shift of the equilibrium causes the enhanced activation of G protein by A2AAR. These findings provide insights into the control of neurotransmissions by A2AAR and the effects of lipids on various GPCR functions.