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

Abstract

The heterogenous and dynamic constitution of the membrane fine-tunes signal transduction.In particular, the polyunsaturated fatty acid (PUFA) tails of phospholipids influence the biophysical properties of the membrane, production of second messengers, or membrane partitioning. Few evidence mostly originating from studies of rhodopsin suggest that PUFAs directly modulate the conformational dynamic of transmembrane proteins. However, whether such properties translate to other G protein-coupled receptors remains unclear. We focused on the dopamine D2 receptor (D2R), a main target of antipsychotics. Membrane enrichment in n-3, but not n-6, PUFAs potentiates ligand binding. Molecular dynamics simulations show that the D2R preferentially interacts with n-3 over n-6 PUFAs. Furthermore, even though this mildly affects signalling in heterologous systems, in vivo n-3 PUFA deficiency blunts the effects of D2R ligands. These results suggest that n-3 PUFAs act as allosteric modulators of the D2R and provide a putative mechanism for their potentiating effect on antipsychotic efficacy.

Membrane lipid poly-unsaturation selectively affects ligand induced dopamine D2 receptor internalization

“…Consequently, Tfn endocytosis was increased in RPE-1 cells (Pinot et al , 2014). Despite a similar level of PUFA enrichment in our protocol (Jobin et al 2023; Baccouch et al 2023; this study) and in Pinot et al (2014), we found that PUFA enrichment in HEK 293 cells did not affect Tfn internalization, arguing against a general effect of PUFA enrichment on endocytosis. Instead, PUFA enrichment specifically inhibits D2R endocytosis, leaving the endocytosis of another class A GPCR, β2AR, unaffected.…”

“…Firstly, PUFA-containing phospholipids could specifically interact with and form a corona around D2Rs within the plasma membrane, affecting its conformation or diffusion in the plasma membrane. This possibility is corroborated by molecular modelling showing that PUFA tails preferentially interact with the D2R when compared to saturated ones (Guixà-González et al , 2016; Jobin et al , 2023). Such a preferential interaction with polyunsaturated chains of phospholipids has been described, using molecular modelling approaches, for other class A GPCRs including rhodopsin (Soubias et al , 2006) and the adenosine A 2A receptor (Leonard & Lyman, 2021; Yang & Lyman, 2019).…”

“…To assess the potential effects of membrane PUFAs on D2R trafficking, we used the protocol developed in (Jobin et al , 2023) to enrich membrane phospholipids with selected FAs, namely DHA, DPA and the saturated fatty acid (SFA) behenic acid (BA), that displays the same carbon chain length (22) as DHA and DPA (Figure EV1A). Incubation with 30 µM of DHA or DPA increased the contents of PUFAs in phospholipids, from 8.6 % in control (EtOH) to ∼14 % in cells treated with DHA or DPA (Figure EV1B), while incubation with 30 µM of BA increased the content of SFA in phospholipids from 34.7% in control (EtOH) to 39.7% in BA treated cells (Figure EV1C).…”

“…Mechanistically, molecular dynamics simulations show that membrane PUFA levels modulate the membrane diffusion rate of the D2R (Guixà-González et al , 2016). Moreover, enrichment in PUFAs in HEK 293 cells alters D2R ligand binding and signaling (Jobin et al , 2023). Altogether, these findings suggest a direct link between membrane PUFAs and the activity of the D2R.…”

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

“…Although all antipsychotics share the common feature represented by D2R occupancy, which is considered the major mechanism of the “anti-psychotic” effect, in recent years, other cellular mechanisms based on dopaminergic function, its modulation, and non-canonical type have emerged [ 46 , 67 , 174 , 349 , 561 , 562 ]. Greater precision in defining the molecular and structural nature of dopamine receptors’ interaction with the antipsychotic molecules (e.g., the atomistic molecular dynamics simulations of typical and atypical antipsychotics and the cryoelectronic microscopy structures of D1R-G s and D2R-G i signaling complexes) has also open new avenues to understanding the “dopaminergic side” of antipsychotic action allowing [ 563 , 564 ].…”