Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences: Implications for im...

Autores
Casadó Anguera, Verònica; Moreno, Estefanía; Sánchez Soto, Marta; Cai, Ning Sheng; Bonaventura, Jordi; Homar Ruano, Patricia; Rubinstein, Marcelo; Cortés, Antoni; Canela, Enric I.; Ferré, Sergi; Casadó, Vicent
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Polymorphic alleles of the human dopamine D4 receptor gene (DRD4) have been consistently associated with individual differences in personality traits and neuropsychiatric disorders, particularly between the gene encoding dopamine D4.7 receptor variant and attention deficit hyperactivity disorder (ADHD). The α2A adrenoceptor gene has also been associated with ADHD. In fact, drugs targeting the α2A adrenoceptor (α2AR), such as guanfacine, are commonly used in ADHD treatment. In view of the involvement of dopamine D4 receptor (D4R) and α2AR in ADHD and impulsivity, their concurrent localization in cortical pyramidal neurons and the demonstrated ability of D4R to form functional heteromers with other G protein-coupled receptors, in this study we evaluate whether the α2AR forms functional heteromers with D4R and weather these heteromers show different properties depending on the D4R variant involved. Using cortical brain slices from hD4.7R knock-in and wild-type mice, here, we demonstrate that α2AR and D4R heteromerize and constitute a significant functional population of cortical α2AR and D4R. Moreover, in cortical slices from wild-type mice and in cells transfected with α2AR and D4.4R, we detect a negative crosstalk within the heteromer. This negative crosstalk is lost in cortex from hD4.7R knock-in mice and in cells expressing the D4.7R polymorphic variant. We also show a lack of efficacy of D4R ligands to promote G protein activation and signaling only within the α2AR-D4.7R heteromer. Taken together, our results suggest that α2AR-D4R heteromers play a pivotal role in catecholaminergic signaling in the brain cortex and are likely targets for ADHD pharmacotherapy.
Fil: Casadó Anguera, Verònica. Universidad de Barcelona; España
Fil: Moreno, Estefanía. Universidad de Barcelona; España
Fil: Sánchez Soto, Marta. National Institutes of Health; Estados Unidos
Fil: Cai, Ning Sheng. National Institutes of Health; Estados Unidos
Fil: Bonaventura, Jordi. National Institutes of Health; Estados Unidos
Fil: Homar Ruano, Patricia. Universidad de Barcelona; España
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Cortés, Antoni. Universidad de Barcelona; España
Fil: Canela, Enric I.. Universidad de Barcelona; España
Fil: Ferré, Sergi. National Institutes of Health; Estados Unidos
Fil: Casadó, Vicent. Universidad de Barcelona; España
Materia
α2A adrenoceptor
ADHD
Cerebral cortex
Dopamine D4 receptor
GPCR
Receptor heteromer
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/158974
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/158974
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences: Implications for impulsive-control disordersCasadó Anguera, VerònicaMoreno, EstefaníaSánchez Soto, MartaCai, Ning ShengBonaventura, JordiHomar Ruano, PatriciaRubinstein, MarceloCortés, AntoniCanela, Enric I.Ferré, SergiCasadó, Vicentα2A adrenoceptorADHDCerebral cortexDopamine D4 receptorGPCRReceptor heteromerhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Polymorphic alleles of the human dopamine D4 receptor gene (DRD4) have been consistently associated with individual differences in personality traits and neuropsychiatric disorders, particularly between the gene encoding dopamine D4.7 receptor variant and attention deficit hyperactivity disorder (ADHD). The α2A adrenoceptor gene has also been associated with ADHD. In fact, drugs targeting the α2A adrenoceptor (α2AR), such as guanfacine, are commonly used in ADHD treatment. In view of the involvement of dopamine D4 receptor (D4R) and α2AR in ADHD and impulsivity, their concurrent localization in cortical pyramidal neurons and the demonstrated ability of D4R to form functional heteromers with other G protein-coupled receptors, in this study we evaluate whether the α2AR forms functional heteromers with D4R and weather these heteromers show different properties depending on the D4R variant involved. Using cortical brain slices from hD4.7R knock-in and wild-type mice, here, we demonstrate that α2AR and D4R heteromerize and constitute a significant functional population of cortical α2AR and D4R. Moreover, in cortical slices from wild-type mice and in cells transfected with α2AR and D4.4R, we detect a negative crosstalk within the heteromer. This negative crosstalk is lost in cortex from hD4.7R knock-in mice and in cells expressing the D4.7R polymorphic variant. We also show a lack of efficacy of D4R ligands to promote G protein activation and signaling only within the α2AR-D4.7R heteromer. Taken together, our results suggest that α2AR-D4R heteromers play a pivotal role in catecholaminergic signaling in the brain cortex and are likely targets for ADHD pharmacotherapy.Fil: Casadó Anguera, Verònica. Universidad de Barcelona; EspañaFil: Moreno, Estefanía. Universidad de Barcelona; EspañaFil: Sánchez Soto, Marta. National Institutes of Health; Estados UnidosFil: Cai, Ning Sheng. National Institutes of Health; Estados UnidosFil: Bonaventura, Jordi. National Institutes of Health; Estados UnidosFil: Homar Ruano, Patricia. Universidad de Barcelona; EspañaFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Cortés, Antoni. Universidad de Barcelona; EspañaFil: Canela, Enric I.. Universidad de Barcelona; EspañaFil: Ferré, Sergi. National Institutes of Health; Estados UnidosFil: Casadó, Vicent. Universidad de Barcelona; EspañaAcademic Press Ltd - Elsevier Science Ltd2021-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/158974Casadó Anguera, Verònica; Moreno, Estefanía; Sánchez Soto, Marta; Cai, Ning Sheng; Bonaventura, Jordi; et al.; Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences: Implications for impulsive-control disorders; Academic Press Ltd - Elsevier Science Ltd; Pharmacological Research; 170; 8-2021; 1-171043-66181096-1186CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S1043661821003297?via%3Dihubinfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.phrs.2021.105745info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:18:00Zoai:ri.conicet.gov.ar:11336/158974instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 12:18:00.819CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences: Implications for impulsive-control disorders
title Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences: Implications for impulsive-control disorders
spellingShingle Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences: Implications for impulsive-control disorders
Casadó Anguera, Verònica
α2A adrenoceptor
ADHD
Cerebral cortex
Dopamine D4 receptor
GPCR
Receptor heteromer
title_short Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences: Implications for impulsive-control disorders
title_full Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences: Implications for impulsive-control disorders
title_fullStr Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences: Implications for impulsive-control disorders
title_full_unstemmed Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences: Implications for impulsive-control disorders
title_sort Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences: Implications for impulsive-control disorders
dc.creator.none.fl_str_mv Casadó Anguera, Verònica
Moreno, Estefanía
Sánchez Soto, Marta
Cai, Ning Sheng
Bonaventura, Jordi
Homar Ruano, Patricia
Rubinstein, Marcelo
Cortés, Antoni
Canela, Enric I.
Ferré, Sergi
Casadó, Vicent
author Casadó Anguera, Verònica
author_facet Casadó Anguera, Verònica
Moreno, Estefanía
Sánchez Soto, Marta
Cai, Ning Sheng
Bonaventura, Jordi
Homar Ruano, Patricia
Rubinstein, Marcelo
Cortés, Antoni
Canela, Enric I.
Ferré, Sergi
Casadó, Vicent
author_role author
author2 Moreno, Estefanía
Sánchez Soto, Marta
Cai, Ning Sheng
Bonaventura, Jordi
Homar Ruano, Patricia
Rubinstein, Marcelo
Cortés, Antoni
Canela, Enric I.
Ferré, Sergi
Casadó, Vicent
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv α2A adrenoceptor
ADHD
Cerebral cortex
Dopamine D4 receptor
GPCR
Receptor heteromer
topic α2A adrenoceptor
ADHD
Cerebral cortex
Dopamine D4 receptor
GPCR
Receptor heteromer
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Polymorphic alleles of the human dopamine D4 receptor gene (DRD4) have been consistently associated with individual differences in personality traits and neuropsychiatric disorders, particularly between the gene encoding dopamine D4.7 receptor variant and attention deficit hyperactivity disorder (ADHD). The α2A adrenoceptor gene has also been associated with ADHD. In fact, drugs targeting the α2A adrenoceptor (α2AR), such as guanfacine, are commonly used in ADHD treatment. In view of the involvement of dopamine D4 receptor (D4R) and α2AR in ADHD and impulsivity, their concurrent localization in cortical pyramidal neurons and the demonstrated ability of D4R to form functional heteromers with other G protein-coupled receptors, in this study we evaluate whether the α2AR forms functional heteromers with D4R and weather these heteromers show different properties depending on the D4R variant involved. Using cortical brain slices from hD4.7R knock-in and wild-type mice, here, we demonstrate that α2AR and D4R heteromerize and constitute a significant functional population of cortical α2AR and D4R. Moreover, in cortical slices from wild-type mice and in cells transfected with α2AR and D4.4R, we detect a negative crosstalk within the heteromer. This negative crosstalk is lost in cortex from hD4.7R knock-in mice and in cells expressing the D4.7R polymorphic variant. We also show a lack of efficacy of D4R ligands to promote G protein activation and signaling only within the α2AR-D4.7R heteromer. Taken together, our results suggest that α2AR-D4R heteromers play a pivotal role in catecholaminergic signaling in the brain cortex and are likely targets for ADHD pharmacotherapy.
Fil: Casadó Anguera, Verònica. Universidad de Barcelona; España
Fil: Moreno, Estefanía. Universidad de Barcelona; España
Fil: Sánchez Soto, Marta. National Institutes of Health; Estados Unidos
Fil: Cai, Ning Sheng. National Institutes of Health; Estados Unidos
Fil: Bonaventura, Jordi. National Institutes of Health; Estados Unidos
Fil: Homar Ruano, Patricia. Universidad de Barcelona; España
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Cortés, Antoni. Universidad de Barcelona; España
Fil: Canela, Enric I.. Universidad de Barcelona; España
Fil: Ferré, Sergi. National Institutes of Health; Estados Unidos
Fil: Casadó, Vicent. Universidad de Barcelona; España
description Polymorphic alleles of the human dopamine D4 receptor gene (DRD4) have been consistently associated with individual differences in personality traits and neuropsychiatric disorders, particularly between the gene encoding dopamine D4.7 receptor variant and attention deficit hyperactivity disorder (ADHD). The α2A adrenoceptor gene has also been associated with ADHD. In fact, drugs targeting the α2A adrenoceptor (α2AR), such as guanfacine, are commonly used in ADHD treatment. In view of the involvement of dopamine D4 receptor (D4R) and α2AR in ADHD and impulsivity, their concurrent localization in cortical pyramidal neurons and the demonstrated ability of D4R to form functional heteromers with other G protein-coupled receptors, in this study we evaluate whether the α2AR forms functional heteromers with D4R and weather these heteromers show different properties depending on the D4R variant involved. Using cortical brain slices from hD4.7R knock-in and wild-type mice, here, we demonstrate that α2AR and D4R heteromerize and constitute a significant functional population of cortical α2AR and D4R. Moreover, in cortical slices from wild-type mice and in cells transfected with α2AR and D4.4R, we detect a negative crosstalk within the heteromer. This negative crosstalk is lost in cortex from hD4.7R knock-in mice and in cells expressing the D4.7R polymorphic variant. We also show a lack of efficacy of D4R ligands to promote G protein activation and signaling only within the α2AR-D4.7R heteromer. Taken together, our results suggest that α2AR-D4R heteromers play a pivotal role in catecholaminergic signaling in the brain cortex and are likely targets for ADHD pharmacotherapy.
publishDate 2021
dc.date.none.fl_str_mv 2021-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/158974
Casadó Anguera, Verònica; Moreno, Estefanía; Sánchez Soto, Marta; Cai, Ning Sheng; Bonaventura, Jordi; et al.; Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences: Implications for impulsive-control disorders; Academic Press Ltd - Elsevier Science Ltd; Pharmacological Research; 170; 8-2021; 1-17
1043-6618
1096-1186
CONICET Digital
CONICET
url http://hdl.handle.net/11336/158974
identifier_str_mv Casadó Anguera, Verònica; Moreno, Estefanía; Sánchez Soto, Marta; Cai, Ning Sheng; Bonaventura, Jordi; et al.; Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences: Implications for impulsive-control disorders; Academic Press Ltd - Elsevier Science Ltd; Pharmacological Research; 170; 8-2021; 1-17
1043-6618
1096-1186
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S1043661821003297?via%3Dihub
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.phrs.2021.105745
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Academic Press Ltd - Elsevier Science Ltd
publisher.none.fl_str_mv Academic Press Ltd - Elsevier Science Ltd
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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