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Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A(2A) and dopamine D(2) receptors

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 re...

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Autores principales: Guixà-González, Ramon, Javanainen, Matti, Gómez-Soler, Maricel, Cordobilla, Begoña, Domingo, Joan Carles, Sanz, Ferran, Pastor, Manuel, Ciruela, Francisco, Martinez-Seara, Hector, Selent, Jana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726318/
https://www.ncbi.nlm.nih.gov/pubmed/26796668
http://dx.doi.org/10.1038/srep19839
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author Guixà-González, Ramon
Javanainen, Matti
Gómez-Soler, Maricel
Cordobilla, Begoña
Domingo, Joan Carles
Sanz, Ferran
Pastor, Manuel
Ciruela, Francisco
Martinez-Seara, Hector
Selent, Jana
author_facet Guixà-González, Ramon
Javanainen, Matti
Gómez-Soler, Maricel
Cordobilla, Begoña
Domingo, Joan Carles
Sanz, Ferran
Pastor, Manuel
Ciruela, Francisco
Martinez-Seara, Hector
Selent, Jana
author_sort Guixà-González, Ramon
collection PubMed
description 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 A(2A) and dopamine D(2) receptor oligomers. Using extensive multiscale computer modelling, we find a marked propensity of DHA for interaction with both A(2A) and D(2) 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 A(2A) and D(2) 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.
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spelling pubmed-47263182016-01-27 Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A(2A) and dopamine D(2) receptors Guixà-González, Ramon Javanainen, Matti Gómez-Soler, Maricel Cordobilla, Begoña Domingo, Joan Carles Sanz, Ferran Pastor, Manuel Ciruela, Francisco Martinez-Seara, Hector Selent, Jana Sci Rep Article 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 A(2A) and dopamine D(2) receptor oligomers. Using extensive multiscale computer modelling, we find a marked propensity of DHA for interaction with both A(2A) and D(2) 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 A(2A) and D(2) 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. Nature Publishing Group 2016-01-22 /pmc/articles/PMC4726318/ /pubmed/26796668 http://dx.doi.org/10.1038/srep19839 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This 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. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Guixà-González, Ramon
Javanainen, Matti
Gómez-Soler, Maricel
Cordobilla, Begoña
Domingo, Joan Carles
Sanz, Ferran
Pastor, Manuel
Ciruela, Francisco
Martinez-Seara, Hector
Selent, Jana
Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A(2A) and dopamine D(2) receptors
title Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A(2A) and dopamine D(2) receptors
title_full Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A(2A) and dopamine D(2) receptors
title_fullStr Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A(2A) and dopamine D(2) receptors
title_full_unstemmed Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A(2A) and dopamine D(2) receptors
title_short Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A(2A) and dopamine D(2) receptors
title_sort membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine a(2a) and dopamine d(2) receptors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726318/
https://www.ncbi.nlm.nih.gov/pubmed/26796668
http://dx.doi.org/10.1038/srep19839
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