Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling.
Mol Psychiatry. 2023-01-06; :
DOI: 10.1038/s41380-022-01928-6
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Jobin ML(#)(1), De Smedt-Peyrusse V(#)(1), Ducrocq F(1), Baccouch R(2), Oummadi
A(1), Pedersen MH(3)(4), Medel-Lacruz B(5), Angelo MF(1), Villette S(2), Van
Delft P(6), Fouillen L(6), Mongrand S(6), Selent J(5), Tolentino-Cortez T(7),
Barreda-Gómez G(7), Grégoire S(8), Masson E(8), Durroux T(9), Javitch
JA(3)(4)(10), Guixà-González R(11), Alves ID(12), Trifilieff P(13).
Author information:
(1)Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux,
France.
(2)Institute of Chemistry & Biology of Membranes & Nanoobjects, CNRS UMR 5248,
Université de Bordeaux, Bordeaux INP, 33600, Pessac, France.
(3)Department of Psychiatry, Columbia University Vagelos College of Physicians
and Surgeons, New York, NY, 10032, USA.
(4)Division of Molecular Therapeutics, New York State Psychiatric Institute, New
York, NY, 10032, USA.
(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.
(6)Laboratory of Membrane Biogenesis (LBM), Research Mix Unity (UMR) 5200,
National Scientific Research Center (CNRS), University of Bordeaux, Bordeaux,
France.
(7)Research Department, IMG Pharma Biotech S.L., BIC Bizkaia (612), 48160,
Derio, Spain.
(8)Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE,
Université Bourgogne Franche-Comté, 21000, Dijon, France.
(9)Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM,
Montpellier, France.
(10)Department of Molecular Pharmacology and Therapeutics, Columbia University
Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA.
(11)Condensed Matter Theory Group, Paul Scherrer Institute (PSI), 5232,
Villigen, PSI, Switzerland. .
(12)Institute of Chemistry & Biology of Membranes & Nanoobjects, CNRS UMR 5248,
Université de Bordeaux, Bordeaux INP, 33600, Pessac, France.
.
(13)Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 33000, Bordeaux,
France. .
(#)Contributed equally
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.