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.

The impact of lipid polyunsaturation on the physical and mechanical properties of lipid membranes

“…Besides, to account for the wide diversity of PUFAs, variations of those membrane properties were investigated upon treatment with PUFAs and PUFA-PLs harboring different number of double bonds and differing in the location of their first double bond (3 and 6). Importantly, previous studies [42] have demonstrated that the incubation of cells with PUFAs allows for their incorporation into cellular membranes, mostly in PC and PE, with a 5-10% enrichment level closely resembling the deficiency levels observed in patients suffering from psychiatric disorders [67]. By means of Raman imaging, we here further revealed that PUFA only accumulate in the plasma membrane, rather than in other intracellular organelles membrane.…”

“…Indeed, current studies by our team on PUFA-enriched cells have revealed PUFAs to function as allosteric modulators of the Dopamine D2 receptor, one of the major targets of antipsychotic (AP) drugs [42]. Moreover, membrane unsaturation can directly modulate the interaction of AP with the receptor.…”

“…Lipidomic analysis performed in total cell membranes have previously revealed the efficient incorporation of DHA, DPA and AA [42] in cell membranes, up to a 10% enrichment-level. However, the precise cellular location of those PUFAs remains elusive.…”