JOBIN, Marie-Lise; DE SMEDT-PEYRUSSE, Veronique; DUCROCQ, Fabien; BACCOUCH, Rim; OUMMADI, Asma; PEDERSEN, Maria; MEDEL-LACRUZ, Brian; ANGELO, Maria-Florencia; VILLETTE, Sandrine; VAN DELFT, Pierre; FOUILLEN, Laetitia; MONGRAND, Sébastien; SELENT, Jana; TOLENTINO-CORTEZ, Tarson; BARREDA-GOMEZ, Gabriel; GREGOIRE, Stephane; MASSON, Elodie; DURROUX, Thierry; JAVITCH, Jonathan; GUIXA-GONZALEZ, Ramon; ALVES, Isabel D.; TRIFILIEFF, Pierre

doi:10.1038/s41380-022-01928-6

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JOBIN, Marie-Lise

Nutrition et Neurobiologie intégrée [NutriNeuro]

DE SMEDT-PEYRUSSE, Veronique
Nutrition et Neurobiologie intégrée [NutriNeuro]

DUCROCQ, Fabien
Nutrition et Neurobiologie intégrée [NutriNeuro]

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Article de revue

Ce document a été publié dans

Molecular Psychiatry. 2023-05, vol. 28, n° 5, p. 1960-1969

Résumé en anglais

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.< Réduire

Mots clés en anglais

Cell biology

Psychiatric disorders

URI

https://oskar-bordeaux.fr/handle/20.500.12278/199278

DOI

http://dx.doi.org/10.1038/s41380-022-01928-6

Project ANR

Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation - ANR-11-INBS-0010
Impact de la composition lipidique membranaire sur la transmission dopaminergique dépendante du récepteur D2 et la motivation
Role du biostatus en acides gras polyinsaturés dans les troubles de contrôle exécutif
Impacte de la poly-insaturation phospholipidique dans la dynamique, l'activation et la signalisation du récepteur Dopamine D2
Initiative d'excellence de l'Université de Bordeaux - ANR-10-IDEX-0003

Unités de recherche

CBMN : Chimie & de Biologie des Membranes & des Nano-objets - UMR 5248