Activation of adenosine A_2A receptor by lipids from docosahexaenoic acid revealed by NMR.

Abstract

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_2AAR) is located in the lipid bilayers of cells, containing acyl chains derived from docosahexaenoic acid (DHA). For the NMR studies, we prepared A_2AAR 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_2AAR. Our NMR studies revealed that the DHA chains redistribute the multiple conformations of A_2AAR toward those preferable for G protein binding. In these conformations, the rotational angle of transmembrane helix 6 is similar to that in the A_2AAR-G protein complex, suggesting that the population shift of the equilibrium causes the enhanced activation of G protein by A_2AAR. These findings provide insights into the control of neurotransmissions by A_2AAR and the effects of lipids on various GPCR functions.