Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptors

Guixà González, Ramon, 1978-; Javanainen, Matti; Gómez Soler, Maricel; Cordobilla, Begoña; Domingo, Joan Carles; Sanz, Ferran; Pastor Maeso, Manuel; Ciruela, Francisco; Martínez Seara, Hector; Selent, Jana

Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptors

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dc.contributor.author Guixà González, Ramon, 1978-ca
dc.contributor.author Javanainen, Mattica
dc.contributor.author Gómez Soler, Maricelca
dc.contributor.author Cordobilla, Begoñaca
dc.contributor.author Domingo, Joan Carlesca
dc.contributor.author Sanz, Ferranca
dc.contributor.author Pastor Maeso, Manuelca
dc.contributor.author Ciruela, Franciscoca
dc.contributor.author Martínez Seara, Hectorca
dc.contributor.author Selent, Janaca
dc.date.accessioned 2016-03-07T14:59:10Z
dc.date.available 2016-03-07T14:59:10Z
dc.date.issued 2016
dc.description.abstract 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 diseaseca
dc.description.sponsorship 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).
dc.format.mimetype application/pdfca
dc.identifier.citation Guixà-González R, Javanainen M, Gómez-Soler M, Cordobilla B, Domingo JC, Sanz F et al. Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptors. Scientific Reports. 2016; 6: 19839. DOI 10.1038/srep19839ca
dc.identifier.doi http://dx.doi.org/10.1038/srep19839
dc.identifier.issn 2045-2322
dc.identifier.uri http://hdl.handle.net/10230/25978
dc.language.iso engca
dc.publisher Nature Publishing Groupca
dc.relation.ispartof Scientific Reports. 2016; 6: 19839
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2009-13609-C04-04
dc.rights © Nature Publishing Group. http://www.nature.com/articles/srep19839/nThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.ca
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.rights.uri http://creativecommons.org/licenses/by/4.0/ca
dc.subject.other Àcids grassosca
dc.subject.other Dopamina -- Receptorsca
dc.title Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptorsca
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersionca

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