Next Article in Journal
Investigating the Role of BATF3 in Grass Carp (Ctenopharyngodon idella) Immune Modulation: A Fundamental Functional Analysis
Next Article in Special Issue
Structural Insights into CB1 Receptor Biased Signaling
Previous Article in Journal
N-Terminal Domain Mediated Regulation of RORα1 Inhibits Invasive Growth in Prostate Cancer
Previous Article in Special Issue
Beyond the Flavour: The Potential Druggability of Chemosensory G Protein-Coupled Receptors
Open AccessArticle

Distinct Dopamine D2 Receptor Antagonists Differentially Impact D2 Receptor Oligomerization

1
Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
2
Laboratory of Molecular Neuropharmacology and Bioinformatics, Unitat de Bioestadística, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
3
Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
4
Unitat de Neurociència Traslacional, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT), Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(7), 1686; https://doi.org/10.3390/ijms20071686
Received: 27 February 2019 / Revised: 27 March 2019 / Accepted: 2 April 2019 / Published: 4 April 2019
(This article belongs to the Special Issue GPCR Structure and Function in Disease)
Dopamine D2 receptors (D2R) are known to form transient homodimer complexes, of which the increased formation has already been associated with development of schizophrenia. Pharmacological targeting and modulation of the equilibrium of these receptor homodimers might lead to a better understanding of the critical role played by these complexes in physiological and pathological conditions. Whereas agonist addition has shown to prolong the D2R dimer lifetime and increase the level of dimer formation, the possible influence of D2R antagonists on dimerization has remained rather unexplored. Here, using a live-cell reporter assay based on the functional complementation of a split Nanoluciferase, a panel of six D2R antagonists were screened for their ability to modulate the level of D2LR dimer formation. Incubation with the D2R antagonist spiperone decreased the level of D2LR dimer formation significantly by 40–60% in real-time and after long-term (≥16 h) incubations. The fact that dimer formation of the well-studied A2a–D2LR dimer was not altered following incubation with spiperone supports the specificity of this observation. Other D2R antagonists, such as clozapine, risperidone, and droperidol did not significantly evoke this dissociation event. Furthermore, molecular modeling reveals that spiperone presents specific Tyr1995.48 and Phe3906.52 conformations, compared to clozapine, which may determine D2R homodimerization. View Full-Text
Keywords: G protein-coupled receptor (GPCR); dimerization; oligomerization; protein complementation assay; NanoLuc binary technology (NanoBiT); dopamine D2 receptor G protein-coupled receptor (GPCR); dimerization; oligomerization; protein complementation assay; NanoLuc binary technology (NanoBiT); dopamine D2 receptor
Show Figures

Graphical abstract

MDPI and ACS Style

Wouters, E.; Marín, A.R.; Dalton, J.A.R.; Giraldo, J.; Stove, C. Distinct Dopamine D2 Receptor Antagonists Differentially Impact D2 Receptor Oligomerization. Int. J. Mol. Sci. 2019, 20, 1686.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop