Distinct Dopamine D-2 Receptor Antagonists Differentially Impact D-2 Receptor Oligomerization

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...

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Autores: Wouters, E, Marin, AR, Dalton, JAR, Giraldo, J, Stove, C
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Institut d'Investigació i Innovació Parc Taulí (I3PT)
Repositorio:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
OAI Identifier:oai:i3pt.fundanetsuite.com:p3024
Acceso en línea:https://i3pt.portalinvestigacion.com/publicaciones/3024
Access Level:acceso abierto
Palabra clave:G protein-coupled receptor (GPCR)
dimerization
oligomerization
protein complementation assay
NanoLuc binary technology (NanoBiT)
dopamine D-2 receptor
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spelling Distinct Dopamine D-2 Receptor Antagonists Differentially Impact D-2 Receptor OligomerizationWouters, EMarin, ARDalton, JARGiraldo, JStove, CG protein-coupled receptor (GPCR)dimerizationoligomerizationprotein complementation assayNanoLuc binary technology (NanoBiT)dopamine D-2 receptorDopamine 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.MDPI2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://i3pt.portalinvestigacion.com/publicaciones/3024INTERNATIONAL JOURNAL OF MOLECULAR SCIENCESISSN: 16616596ISSNe: 14220067reponame:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulíinstname:Institut d'Investigació i Innovació Parc Taulí (I3PT)Inglésinfo:eu-repo/semantics/openAccessoai:i3pt.fundanetsuite.com:p30242026-06-21T15:30:37Z
dc.title.none.fl_str_mv Distinct Dopamine D-2 Receptor Antagonists Differentially Impact D-2 Receptor Oligomerization
title Distinct Dopamine D-2 Receptor Antagonists Differentially Impact D-2 Receptor Oligomerization
spellingShingle Distinct Dopamine D-2 Receptor Antagonists Differentially Impact D-2 Receptor Oligomerization
Wouters, E
G protein-coupled receptor (GPCR)
dimerization
oligomerization
protein complementation assay
NanoLuc binary technology (NanoBiT)
dopamine D-2 receptor
title_short Distinct Dopamine D-2 Receptor Antagonists Differentially Impact D-2 Receptor Oligomerization
title_full Distinct Dopamine D-2 Receptor Antagonists Differentially Impact D-2 Receptor Oligomerization
title_fullStr Distinct Dopamine D-2 Receptor Antagonists Differentially Impact D-2 Receptor Oligomerization
title_full_unstemmed Distinct Dopamine D-2 Receptor Antagonists Differentially Impact D-2 Receptor Oligomerization
title_sort Distinct Dopamine D-2 Receptor Antagonists Differentially Impact D-2 Receptor Oligomerization
dc.creator.none.fl_str_mv Wouters, E
Marin, AR
Dalton, JAR
Giraldo, J
Stove, C
author Wouters, E
author_facet Wouters, E
Marin, AR
Dalton, JAR
Giraldo, J
Stove, C
author_role author
author2 Marin, AR
Dalton, JAR
Giraldo, J
Stove, C
author2_role author
author
author
author
dc.subject.none.fl_str_mv G protein-coupled receptor (GPCR)
dimerization
oligomerization
protein complementation assay
NanoLuc binary technology (NanoBiT)
dopamine D-2 receptor
topic G protein-coupled receptor (GPCR)
dimerization
oligomerization
protein complementation assay
NanoLuc binary technology (NanoBiT)
dopamine D-2 receptor
description 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.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://i3pt.portalinvestigacion.com/publicaciones/3024
url https://i3pt.portalinvestigacion.com/publicaciones/3024
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN: 16616596
ISSNe: 14220067
reponame:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
instname:Institut d'Investigació i Innovació Parc Taulí (I3PT)
instname_str Institut d'Investigació i Innovació Parc Taulí (I3PT)
reponame_str r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
collection r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
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