Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling.

Autor: Jobin ML; Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France., De Smedt-Peyrusse V; Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France., Ducrocq F; Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France., Baccouch R; Institute of Chemistry & Biology of Membranes & Nanoobjects, CNRS UMR 5248, Université de Bordeaux, Bordeaux INP, 33600, Pessac, France., Oummadi A; Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France., Pedersen MH; Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, 10032, USA., Medel-Lacruz B; Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM)-Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), 08003, Barcelona, Spain., Angelo MF; Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France., Villette S; Institute of Chemistry & Biology of Membranes & Nanoobjects, CNRS UMR 5248, Université de Bordeaux, Bordeaux INP, 33600, Pessac, France., Van Delft P; Laboratory of Membrane Biogenesis (LBM), Research Mix Unity (UMR) 5200, National Scientific Research Center (CNRS), University of Bordeaux, Bordeaux, France., Fouillen L; Laboratory of Membrane Biogenesis (LBM), Research Mix Unity (UMR) 5200, National Scientific Research Center (CNRS), University of Bordeaux, Bordeaux, France., Mongrand S; Laboratory of Membrane Biogenesis (LBM), Research Mix Unity (UMR) 5200, National Scientific Research Center (CNRS), University of Bordeaux, Bordeaux, France., Selent J; Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM)-Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), 08003, Barcelona, Spain., Tolentino-Cortez T; Research Department, IMG Pharma Biotech S.L., BIC Bizkaia (612), 48160, Derio, Spain., Barreda-Gómez G; Research Department, IMG Pharma Biotech S.L., BIC Bizkaia (612), 48160, Derio, Spain., Grégoire S; Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, 21000, Dijon, France., Masson E; Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, 21000, Dijon, France., Durroux T; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France., Javitch JA; Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, 10032, USA.; Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA., Guixà-González R; Condensed Matter Theory Group, Paul Scherrer Institute (PSI), 5232, Villigen, PSI, Switzerland. ramon.guixa@psi.ch., Alves ID; Institute of Chemistry & Biology of Membranes & Nanoobjects, CNRS UMR 5248, Université de Bordeaux, Bordeaux INP, 33600, Pessac, France. i.alves@cbmn.u-bordeaux.fr., Trifilieff P; Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France. pierre.trifilieff@inrae.fr.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2023 May; Vol. 28 (5), pp. 1960-1969. Date of Electronic Publication: 2023 Jan 06.
DOI: 10.1038/s41380-022-01928-6
Abstrakt: Increasing evidence supports a relationship between lipid metabolism and mental health. In particular, the biostatus of polyunsaturated fatty acids (PUFAs) correlates with some symptoms of psychiatric disorders, as well as the efficacy of pharmacological treatments. Recent findings highlight a direct association between brain PUFA levels and dopamine transmission, a major neuromodulatory system implicated in the etiology of psychiatric symptoms. However, the mechanisms underlying this relationship are still unknown. Here we demonstrate that membrane enrichment in the n-3 PUFA docosahexaenoic acid (DHA), potentiates ligand binding to the dopamine D2 receptor (D2R), suggesting that DHA acts as an allosteric modulator of this receptor. Molecular dynamics simulations confirm that DHA has a high preference for interaction with the D2R and show that membrane unsaturation selectively enhances the conformational dynamics of the receptor around its second intracellular loop. We find that membrane unsaturation spares G protein activity but potentiates the recruitment of β-arrestin in cells. Furthermore, in vivo n-3 PUFA deficiency blunts the behavioral effects of two D2R ligands, quinpirole and aripiprazole. These results highlight the importance of membrane unsaturation for D2R activity and provide a putative mechanism for the ability of PUFAs to enhance antipsychotic efficacy.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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