Membrane levels of docosahexaenoic acid (DHA), an essential omega-3 polyunsaturated fatty acid (?-3 PUFA), are decreased in common neuropsychiatric disorders. DHA modulates key cell membrane properties like fluidity, thereby affecting the behaviour of transmembrane proteins like G protein-coupled receptors (GPCRs). These receptors, which have special relevance for major neuropsychiatric disorders have recently been shown to form dimers or higher order oligomers, and evidence suggests that DHA levels affect GPCR function by modulating oligomerisation. In this study, we assessed the effect of membrane DHA content on the formation of a class of protein complexes with particular relevance for brain disease: adenosine A2A and dopamine D2 receptor oligomers. Using extensive multiscale computer modelling, we find a marked propensity of DHA for interaction with both A2A and D2 receptors, which leads to an increased rate of receptor oligomerisation. Bioluminescence resonance energy transfer (BRET) experiments performed on living cells suggest that this DHA effect on the oligomerisation of A2A and D2 receptors is purely kinetic. This work reveals for the first time that membrane ?-3 PUFAs play a key role in GPCR oligomerisation kinetics, which may have important implications for neuropsychiatric conditions like schizophrenia or Parkinson's disease

J.S. and R.G.-G. acknowledge support from Fundació La Marató de TV3 (091010)/Instituto de Salud Carlos III FEDER (CP12/03139)/Ministerio de Educación y Ciencia (Grant number: SAF2009-13609-C04-04) the GLISTEN European Research Network, and the computer resources, technical expertise and assistance provided by the Red Española de Supercomputación (RES). R.G.-G. was also supported by the HPC-Europa2 project (project number: 228398) with the support of the European Commission - Capacities Area - Research Infrastructures. R.G.-G., M.J. and H.M.-S. thank the CSC–IT Center for Science for the computational resources provided. H.M-S. and M.J. acknowledge financial support from the Academy of Finland through its Centre of Excellence Programme. F.C. acknowledges support from Ministerio de Economía y Competitividad/Instituto de Salud Carlos III (SAF2014-55700-P, PCIN-2013-019-C03-03 and PIE14/00034), Institució Catalana de Recerca i Estudis Avançats (ICREA Academia-2010) and Agentschap voor Innovatie door Wetenschap en Technologie (SBO-140028). Also, M.G.-S. and F.C. belong to the “Neuropharmacology” and “Pain” accredited research group (Generalitat de Catalunya, 2009 SGR 232).