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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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 ; GPCRmd IDs: 1239, 1240, 1241, 1242, and 1243.
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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).
The authors declare no competing interests.
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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 (2023). https://doi.org/10.1038/s41380-022-01928-6