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

Molecular Psychiatry volume 28, pages 1960–1969 (2023)Cite this article

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A Correction to this article was published on 07 August 2023

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Abstract

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.

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Fig. 1: D2R binding affinity in PUFA-enriched cell membranes shown by PWR.
Fig. 2: Lipid-protein contacts during MD simulations and effect on the structure of the D2R.
Fig. 3: Forskolin-stimulated cAMP production and β-arrestin2 recruitment upon D2R ligand stimulation and with different membrane PUFAs enrichment.
Fig. 4: Effect of n-3 PUFA deficiency in vivo on D2R signaling and associated behaviors.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. All MD simulation trajectories generated in this study can be visualized and inspected through the GPCRmd online resource [99]; GPCRmd IDs: 1239, 1240, 1241, 1242, and 1243.

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Acknowledgements

We thank the biochemistry facility of the Bordeaux Neurocampus for the access to the blot imaging system, JJ. Toulmé for use of the fluorescence spectrometer (TECAN), JL. Banères for providing D2R expressing Pichia pastoris and the Bordeaux Metabolome Facility-MetaboHUB (ANR-11-INBS-0010). This study was supported by INRAE, CNRS and the University of Bordeaux; University of Bordeaux’s IdEx “Investments for the future” program/GPR BRAIN_203 (PT), Idex Bordeaux “chaire d’installation” (ANR-10-IDEX-03-02) (PT), NARSAD Young Investigator Grants from the Brain and Behavior Foundation (PT), ANR “SynLip” (ANR-16-CE16-0022) (PT), ANR “FrontoFat” (ANR-20-CE14-0020) (PT), ANR “PolyFADO” (ANR-21-CE44-0019-02) (IA and PT), Region Nouvelle Aquitaine 2014-1R30301-00003023 (PT), Région Nouvelle Aquitaine (2011 13 04 002) (IA), PEPS Emergence Idex Bordeaux (2012) (IA), NIH grant MH54137 (JAJ), the Instituto de Salud Carlos III FEDER (PI18/00094) and the ERA-NET NEURON & Ministry of Economy, Industry and Competitiveness (AC18/00030) (JS), the European Research Network on Signal Transduction (https://ernest-gpcr.eu) (COST Action CA18133) (BM, RG-G, JS), the Swiss National Science Foundation, grant no. 192780 (RG-G).

Author information

Author notes

  1. These authors contributed equally: Marie-Lise Jobin, Véronique De Smedt-Peyrusse.

  2. These authors jointly supervised this work: Ramon Guixà-González, Isabel D. Alves, Pierre Trifilieff.

Authors and Affiliations

  1. Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux, France

    Marie-Lise Jobin, Véronique De Smedt-Peyrusse, Fabien Ducrocq, Asma Oummadi, Maria-Florencia Angelo & Pierre Trifilieff

  2. Institute of Chemistry & Biology of Membranes & Nanoobjects, CNRS UMR 5248, Université de Bordeaux, Bordeaux INP, 33600, Pessac, France

    Rim Baccouch, Sandrine Villette & Isabel D. Alves

  3. Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA

    Maria Hauge Pedersen & Jonathan A. Javitch

  4. Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, 10032, USA

    Maria Hauge Pedersen & Jonathan A. Javitch

  5. 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

    Brian Medel-Lacruz & Jana Selent

  6. Laboratory of Membrane Biogenesis (LBM), Research Mix Unity (UMR) 5200, National Scientific Research Center (CNRS), University of Bordeaux, Bordeaux, France

    Pierre Van Delft, Laetitia Fouillen & Sébastien Mongrand

  7. Research Department, IMG Pharma Biotech S.L., BIC Bizkaia (612), 48160, Derio, Spain

    Tarson Tolentino-Cortez & Gabriel Barreda-Gómez

  8. Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, 21000, Dijon, France

    Stéphane Grégoire & Elodie Masson

  9. Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France

    Thierry Durroux

  10. Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA

    Jonathan A. Javitch

  11. Condensed Matter Theory Group, Paul Scherrer Institute (PSI), 5232, Villigen, PSI, Switzerland

    Ramon Guixà-González

Authors
  1. Marie-Lise Jobin
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  2. Véronique De Smedt-Peyrusse
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  3. Fabien Ducrocq
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  4. Rim Baccouch
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  5. Asma Oummadi
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  6. Maria Hauge Pedersen
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  7. Brian Medel-Lacruz
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  8. Maria-Florencia Angelo
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  9. Sandrine Villette
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  10. Pierre Van Delft
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  11. Laetitia Fouillen
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  12. Sébastien Mongrand
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  13. Jana Selent
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  14. Tarson Tolentino-Cortez
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  15. Gabriel Barreda-Gómez
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  16. Stéphane Grégoire
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  17. Elodie Masson
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  18. Thierry Durroux
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  19. Jonathan A. Javitch
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  20. Ramon Guixà-González
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  21. Isabel D. Alves
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  22. Pierre Trifilieff
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Contributions

M-LJ, VDP, RG-G, IDA and PT conceived and supervised the study. JS, GB-G, EM, TD and JAJ provided expertise, reagents and supervised specific experiments. M-LJ, VDP, FD, AO, RB, M-FA, MHP, BM-L, JS, SM, SV, TT-C, SG and RG-G performed experiments and analyzed the data. M-LJ, VDP, RG-G, IDA and PT wrote the original version of the manuscript. All authors discussed the results and reviewed the manuscript.

Corresponding authors

Correspondence to Ramon Guixà-González, Isabel D. Alves or Pierre Trifilieff.

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The authors declare no competing interests.

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The original online version of this article was revised: In Fig. 3E of this article, the X-axis of the graph was mislabeled.

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Jobin, ML., De Smedt-Peyrusse, V., Ducrocq, F. et al. Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling. Mol Psychiatry 28, 1960–1969 (2023). https://doi.org/10.1038/s41380-022-01928-6

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