Activation of adenosine A(2A) receptor by lipids from docosahexaenoic acid revealed by NMR

The lipid composition of the plasma membrane is a key parameter in controlling signal transduction through G protein–coupled receptors (GPCRs). Adenosine A(2A) receptor (A(2A)AR) is located in the lipid bilayers of cells, containing acyl chains derived from docosahexaenoic acid (DHA). For the NMR studies, we prepared A(2A)AR in lipid bilayers of nanodiscs, containing DHA chains and other acyl chains. The DHA chains in nanodiscs enhanced the activation of G proteins by A(2A)AR. Our NMR studies revealed that the DHA chains redistribute the multiple conformations of A(2A)AR toward those preferable for G protein binding. In these conformations, the rotational angle of transmembrane helix 6 is similar to that in the A(2A)AR–G protein complex, suggesting that the population shift of the equilibrium causes the enhanced activation of G protein by A(2A)AR. These findings provide insights into the control of neurotransmissions by A(2A)AR and the effects of lipids on various GPCR functions.