A new study⁽¹⁾ published in Nature Communications shows that membrane enrichment with two polyunsaturated fatty acids, DHA and DPA, reduces agonist-induced endocytosis of the dopamine D2 receptor, a major target of antipsychotic drugs. By combining confocal microscopy and live-cell TIRF imaging, the researchers showed that D2R clustering at the plasma membrane is preserved, while β-arrestin2 recruitment to D2R endocytic sites and the formation of D2R-containing endocytic vesicles are reduced.

Linking membrane lipids and dopamine receptor trafficking

The brain is highly enriched in polyunsaturated fatty acids, or PUFAs, and altered PUFA levels have been associated with several neuropsychiatric disorders. Previous work had linked dietary PUFA deficiency in mice to behavioural changes, including altered motivation, involving neurons expressing the dopamine D2 receptor (D2R). In this new study, Silvia Sposini et al. investigated whether PUFA levels in cellular membranes could directly affect the trafficking of the D2R, a G protein-coupled receptor involved in dopaminergic signalling and a major target of antipsychotic drugs.

By enriching cell membranes with two different PUFAs, DHA and DPA, the team showed that agonist-induced D2R endocytosis was strongly reduced. This effect was observed in HEK-293 cells and confirmed in cultured cortical neurons. Importantly, PUFA enrichment did not affect clathrin-mediated endocytosis in general, assessed using transferrin uptake, nor the internalization of several other GPCRs tested. These results highlight a specific sensitivity of D2R endocytosis to membrane PUFA levels.

Imaging the altered steps of D2R endocytosis

Microscopy played a key role in understanding this mechanism. Confocal imaging showed that fewer D2R-containing endosomes formed in PUFA-enriched cells after receptor activation. Live-cell TIRF microscopy then allowed the researchers to observe early endocytic events at the plasma membrane. While D2R clustering at endocytic sites remained unchanged, the recruitment of β-arrestin2, an essential protein for D2R endocytosis and signalling, was reduced. Using the pulsed-pH assay, the team further showed a lower frequency of D2R-containing endocytic vesicle formation.

Finally, the study identified two key residues in the second intracellular loop of D2R, serines 147 and 148, as essential for the sensitivity of D2R endocytosis to PUFA levels. When these residues were mutated, the receptor still internalized after activation, but PUFA enrichment no longer reduced its endocytosis.

Together, these results show that membrane lipids do not only influence general membrane properties such as fluidity or rigidity. They can also specifically regulate the trafficking of membrane proteins such as the dopamine D2 receptor. This study opens new perspectives on how membrane composition may influence D2R trafficking, with potential consequences for dopaminergic signalling in the brain.

⁽¹⁾ Sposini, S., Baccouch, R., Lescuyer, M. et al. Membrane lipid poly-unsaturation selectively affects dopamine D2 receptor endocytosis. Nat Commun 17, 6661 (2026). https://doi.org/10.1038/s41467-026-73057-5