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Distinct dopamine D2 receptor antagonists differentially impact D2 receptor oligomerization

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Abstract
Dopamine D-2 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 A(2a)-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 Tyr199(5.48) and Phe390(6.52) conformations, compared to clozapine, which may determine D2R homodimerization.
Keywords
G protein-coupled receptor (GPCR), dimerization, oligomerization, protein complementation assay, NanoLuc binary technology (NanoBiT), dopamine D-2 receptor KeyWords Plus:PROTEIN-COUPLED RECEPTORS, D2 RECEPTOR, CANNABINOID CB1, ALLOSTERIC INTERACTIONS, SURFACE EXPRESSION, FORCE-FIELD, ADENOSINE, DIMERIZATION, DIMER, COMPLEMENTATION

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Citation

Please use this url to cite or link to this publication:

MLA
Wouters, Elise et al. “Distinct Dopamine D2 Receptor Antagonists Differentially Impact D2 Receptor Oligomerization.” INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 20.7 (2019): n. pag. Print.
APA
Wouters, Elise, Marín, A. R., Dalton, J. A. R., Giraldo, J., & Stove, C. (2019). Distinct dopamine D2 receptor antagonists differentially impact D2 receptor oligomerization. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 20(7).
Chicago author-date
Wouters, Elise, Adrián Ricarte Marín, James Andrew Rupert Dalton, Jesús Giraldo, and Christophe Stove. 2019. “Distinct Dopamine D2 Receptor Antagonists Differentially Impact D2 Receptor Oligomerization.” International Journal of Molecular Sciences 20 (7).
Chicago author-date (all authors)
Wouters, Elise, Adrián Ricarte Marín, James Andrew Rupert Dalton, Jesús Giraldo, and Christophe Stove. 2019. “Distinct Dopamine D2 Receptor Antagonists Differentially Impact D2 Receptor Oligomerization.” International Journal of Molecular Sciences 20 (7).
Vancouver
1.
Wouters E, Marín AR, Dalton JAR, Giraldo J, Stove C. Distinct dopamine D2 receptor antagonists differentially impact D2 receptor oligomerization. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. 2019;20(7).
IEEE
[1]
E. Wouters, A. R. Marín, J. A. R. Dalton, J. Giraldo, and C. Stove, “Distinct dopamine D2 receptor antagonists differentially impact D2 receptor oligomerization,” INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 20, no. 7, 2019.
@article{8617059,
  abstract     = {Dopamine D-2 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 A(2a)-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 Tyr199(5.48) and Phe390(6.52) conformations, compared to clozapine, which may determine D2R homodimerization.},
  articleno    = {1686},
  author       = {Wouters, Elise and Marín, Adrián Ricarte  and Dalton, James Andrew Rupert and  Giraldo, Jesús and Stove, Christophe},
  issn         = {1422-0067},
  journal      = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES},
  keywords     = {G protein-coupled receptor (GPCR),dimerization,oligomerization,protein complementation assay,NanoLuc binary technology (NanoBiT),dopamine D-2 receptor   KeyWords Plus:PROTEIN-COUPLED RECEPTORS,D2 RECEPTOR,CANNABINOID CB1,ALLOSTERIC INTERACTIONS,SURFACE EXPRESSION,FORCE-FIELD,ADENOSINE,DIMERIZATION,DIMER,COMPLEMENTATION},
  language     = {eng},
  number       = {7},
  pages        = {25},
  title        = {Distinct dopamine D2 receptor antagonists differentially impact D2 receptor oligomerization},
  url          = {http://dx.doi.org/10.3390/ijms20071686},
  volume       = {20},
  year         = {2019},
}

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