Receptor density influences ligand-induced dopamine D2L receptor homodimerization

• Published in: European journal of pharmacology 2021-11, Vol.911, p.174557, Article 174557
• Main Authors: Ferraiolo, Mattia, Atik, Hicham, Ponthot, Romane, Belo do Nascimento, Inês, Beckers, Pauline, Stove, Christophe, Hermans, Emmanuel
• Format: Article
• Language: English
• Subjects: Antiparkinsonian; Antipsychotic; D2L; Dimers; Dopamine; G protein coupled receptor; Luciferase; Oligomers; Parkinson's disease; Receptor density; Schizophrenia
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174557

Chronic treatments with dopamine D2 receptor ligands induce fluctuations in D2 receptor density. Since D2 receptors tend to assemble as homodimers, we hypothesized that receptor density might influence constitutive and ligand-induced homodimerization. Using a nanoluciferase-based complementation assay to monitor dopamine D2L receptor homodimerization in a cellular model enabling the tetracycline-controlled expression of dopamine D2L receptors, we observed that increasing receptor density promoted constitutive dopamine D2L receptor homodimerization. Receptor full agonists promoted homodimerization, while antagonists and partial agonists disrupted dopamine D2L receptor homodimers. High receptor densities enhanced this inhibitory effect only for receptor antagonists. Taken together, our findings indicate that both receptor density and receptor ligands influence dopamine D2L receptor homodimerization, albeit excluding any strict correlation with ligands’ intrinsic activity and highlighting further complexity to dopaminergic pharmacology. [Display omitted] •Increasing receptor density promotes constitutive D2L homodimerization.•D2L homodimerization is promoted by receptor agonists.•D2 antagonists and partial agonists disrupt D2L homodimers.•Receptor density differentially influences ligand-induced homodimerization.•D2L homodimerization and ligands’ intrinsic activities are not strictly correlated.