title: Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptors.
abstract: Membrane levels of docosahexaenoic acid (DHA), an essential omega-3 polyunsaturated fatty acid (ω-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 ω-3 PUFAs play a key role in GPCR oligomerisation kinetics, which may have important implications for neuropsychiatric conditions like schizophrenia or Parkinson's disease.
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences Universitat Pompeu Fabra, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Guixà-González
authors.affiliation: Department of Physics, Tampere University of Technology, Tampere, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Javanainen
authors.affiliation: Facultat de Medicina, IDIBELL, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Maricel
authors.initials: M
authors.lastname: Gómez-Soler
authors.affiliation: Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Cordobilla
authors.affiliation: Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: Domingo
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences Universitat Pompeu Fabra, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
authors.forename: Ferran
authors.initials: F
authors.lastname: Sanz
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences Universitat Pompeu Fabra, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Pastor
authors.affiliation: Facultat de Medicina, IDIBELL, Universitat de Barcelona, Barcelona, Spain.|Faculty of Sciences, University of Ghent, Gent, Belgium.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
authors.affiliation: Department of Physics, Tampere University of Technology, Tampere, Finland.
authors.forename: Hector
authors.initials: H
authors.lastname: Martinez-Seara
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences Universitat Pompeu Fabra, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
authors.forename: Jana
authors.initials: J
authors.lastname: Selent
mesh_terms: D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004058:Diffusion; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D005227:Fatty Acids / Q000032:analysis; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D010743:Phospholipids / Q000032:analysis; D011336:Probability; D066329:Protein Aggregates / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013997:Time Factors
chemical_list: D005227:Fatty Acids; D015525:Fatty Acids, Omega-3; D010743:Phospholipids; D066329:Protein Aggregates; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D004281:Docosahexaenoic Acids