Dopamine D 4 receptor, but not the ADHD-associated D 4.7 variant, forms functional heteromers with the dopamine D 2S receptor in the brain

Autores
González, S.; Rangel Barajas, C.; Peper, Marcela; Lorenzo Lopez, Juan Ramiro; Moreno, E.; Ciruela, F.; Borycz, J.; Ortiz, J.; Lluís, C.; Franco, R.; McCormick, P. J.; Volkow, N. D.; Rubinstein, Marcelo; Floran, B.; Ferré, S.
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Polymorphic variants of the dopamine D 4 receptor have been consistently associated with attention-deficit hyperactivity disorder (ADHD). However, the functional significance of the risk polymorphism (variable number of tandem repeats in exon 3) is still unclear. Here, we show that whereas the most frequent 4-repeat (D 4.4) and the 2-repeat (D 4.2) variants form functional heteromers with the short isoform of the dopamine D 2 receptor (D 2S), the 7-repeat risk allele (D 4.7) does not. D 2 receptor activation in the D 2S-D 4 receptor heteromer potentiates D 4 receptor-mediated MAPK signaling in transfected cells and in the striatum, which did not occur in cells expressing D 4.7 or in the striatum of knockin mutant mice carrying the 7 repeats of the human D 4.7 in the third intracellular loop of the D 4 receptor. In the striatum, D 4 receptors are localized in corticostriatal glutamatergic terminals, where they selectively modulate glutamatergic neurotransmission by interacting with D 2S receptors. This interaction shows the same qualitative characteristics than the D 2S-D 4 receptor heteromer-mediated mitogen-activated protein kinase (MAPK) signaling and D 2S receptor activation potentiates D 4 receptor-mediated inhibition of striatal glutamate release. It is therefore postulated that dysfunctional D 2S-D 4.7 heteromers may impair presynaptic dopaminergic control of corticostriatal glutamatergic neurotransmission and explain functional deficits associated with ADHD.
Fil: González, S.. Universidad de Barcelona; España
Fil: Rangel Barajas, C.. Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional; México
Fil: Peper, Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Lorenzo Lopez, Juan Ramiro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Moreno, E.. Universidad de Barcelona; España
Fil: Ciruela, F.. Universidad de Barcelona; España
Fil: Borycz, J.. National Institutes of Health; Estados Unidos
Fil: Ortiz, J.. Universitat Autònoma de Barcelona; España
Fil: Lluís, C.. Universidad de Barcelona; España
Fil: Franco, R.. Universidad de Navarra; España
Fil: McCormick, P. J.. Universidad de Barcelona; España
Fil: Volkow, N. D.. National Institutes of Health; Estados Unidos
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: Floran, B.. Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional; México
Fil: Ferré, S.. Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional; México
Materia
Adhd
Dopamine Receptors
Glutamate
Receptor Heteromers
Striatum
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/79394
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/79394
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Dopamine D 4 receptor, but not the ADHD-associated D 4.7 variant, forms functional heteromers with the dopamine D 2S receptor in the brainGonzález, S.Rangel Barajas, C.Peper, MarcelaLorenzo Lopez, Juan RamiroMoreno, E.Ciruela, F.Borycz, J.Ortiz, J.Lluís, C.Franco, R.McCormick, P. J.Volkow, N. D.Rubinstein, MarceloFloran, B.Ferré, S.AdhdDopamine ReceptorsGlutamateReceptor HeteromersStriatumhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Polymorphic variants of the dopamine D 4 receptor have been consistently associated with attention-deficit hyperactivity disorder (ADHD). However, the functional significance of the risk polymorphism (variable number of tandem repeats in exon 3) is still unclear. Here, we show that whereas the most frequent 4-repeat (D 4.4) and the 2-repeat (D 4.2) variants form functional heteromers with the short isoform of the dopamine D 2 receptor (D 2S), the 7-repeat risk allele (D 4.7) does not. D 2 receptor activation in the D 2S-D 4 receptor heteromer potentiates D 4 receptor-mediated MAPK signaling in transfected cells and in the striatum, which did not occur in cells expressing D 4.7 or in the striatum of knockin mutant mice carrying the 7 repeats of the human D 4.7 in the third intracellular loop of the D 4 receptor. In the striatum, D 4 receptors are localized in corticostriatal glutamatergic terminals, where they selectively modulate glutamatergic neurotransmission by interacting with D 2S receptors. This interaction shows the same qualitative characteristics than the D 2S-D 4 receptor heteromer-mediated mitogen-activated protein kinase (MAPK) signaling and D 2S receptor activation potentiates D 4 receptor-mediated inhibition of striatal glutamate release. It is therefore postulated that dysfunctional D 2S-D 4.7 heteromers may impair presynaptic dopaminergic control of corticostriatal glutamatergic neurotransmission and explain functional deficits associated with ADHD.Fil: González, S.. Universidad de Barcelona; EspañaFil: Rangel Barajas, C.. Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional; MéxicoFil: Peper, Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Lorenzo Lopez, Juan Ramiro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Moreno, E.. Universidad de Barcelona; EspañaFil: Ciruela, F.. Universidad de Barcelona; EspañaFil: Borycz, J.. National Institutes of Health; Estados UnidosFil: Ortiz, J.. Universitat Autònoma de Barcelona; EspañaFil: Lluís, C.. Universidad de Barcelona; EspañaFil: Franco, R.. Universidad de Navarra; EspañaFil: McCormick, P. J.. Universidad de Barcelona; EspañaFil: Volkow, N. D.. National Institutes of Health; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Floran, B.. Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional; MéxicoFil: Ferré, S.. Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional; MéxicoNature Publishing Group2012-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/79394González, S.; Rangel Barajas, C.; Peper, Marcela; Lorenzo Lopez, Juan Ramiro; Moreno, E.; et al.; Dopamine D 4 receptor, but not the ADHD-associated D 4.7 variant, forms functional heteromers with the dopamine D 2S receptor in the brain; Nature Publishing Group; Molecular Psychiatry; 17; 6; 6-2012; 650-6621359-4184CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/mp.2011.93info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/mp201193info:eu-repo/semantics/altIdentifier/url/https://pubmed.ncbi.nlm.nih.gov/21844870/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:20:26Zoai:ri.conicet.gov.ar:11336/79394instacron: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:34982025-09-10 13:20:26.256CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Dopamine D 4 receptor, but not the ADHD-associated D 4.7 variant, forms functional heteromers with the dopamine D 2S receptor in the brain
title Dopamine D 4 receptor, but not the ADHD-associated D 4.7 variant, forms functional heteromers with the dopamine D 2S receptor in the brain
spellingShingle Dopamine D 4 receptor, but not the ADHD-associated D 4.7 variant, forms functional heteromers with the dopamine D 2S receptor in the brain
González, S.
Adhd
Dopamine Receptors
Glutamate
Receptor Heteromers
Striatum
title_short Dopamine D 4 receptor, but not the ADHD-associated D 4.7 variant, forms functional heteromers with the dopamine D 2S receptor in the brain
title_full Dopamine D 4 receptor, but not the ADHD-associated D 4.7 variant, forms functional heteromers with the dopamine D 2S receptor in the brain
title_fullStr Dopamine D 4 receptor, but not the ADHD-associated D 4.7 variant, forms functional heteromers with the dopamine D 2S receptor in the brain
title_full_unstemmed Dopamine D 4 receptor, but not the ADHD-associated D 4.7 variant, forms functional heteromers with the dopamine D 2S receptor in the brain
title_sort Dopamine D 4 receptor, but not the ADHD-associated D 4.7 variant, forms functional heteromers with the dopamine D 2S receptor in the brain
dc.creator.none.fl_str_mv González, S.
Rangel Barajas, C.
Peper, Marcela
Lorenzo Lopez, Juan Ramiro
Moreno, E.
Ciruela, F.
Borycz, J.
Ortiz, J.
Lluís, C.
Franco, R.
McCormick, P. J.
Volkow, N. D.
Rubinstein, Marcelo
Floran, B.
Ferré, S.
author González, S.
author_facet González, S.
Rangel Barajas, C.
Peper, Marcela
Lorenzo Lopez, Juan Ramiro
Moreno, E.
Ciruela, F.
Borycz, J.
Ortiz, J.
Lluís, C.
Franco, R.
McCormick, P. J.
Volkow, N. D.
Rubinstein, Marcelo
Floran, B.
Ferré, S.
author_role author
author2 Rangel Barajas, C.
Peper, Marcela
Lorenzo Lopez, Juan Ramiro
Moreno, E.
Ciruela, F.
Borycz, J.
Ortiz, J.
Lluís, C.
Franco, R.
McCormick, P. J.
Volkow, N. D.
Rubinstein, Marcelo
Floran, B.
Ferré, S.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Adhd
Dopamine Receptors
Glutamate
Receptor Heteromers
Striatum
topic Adhd
Dopamine Receptors
Glutamate
Receptor Heteromers
Striatum
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Polymorphic variants of the dopamine D 4 receptor have been consistently associated with attention-deficit hyperactivity disorder (ADHD). However, the functional significance of the risk polymorphism (variable number of tandem repeats in exon 3) is still unclear. Here, we show that whereas the most frequent 4-repeat (D 4.4) and the 2-repeat (D 4.2) variants form functional heteromers with the short isoform of the dopamine D 2 receptor (D 2S), the 7-repeat risk allele (D 4.7) does not. D 2 receptor activation in the D 2S-D 4 receptor heteromer potentiates D 4 receptor-mediated MAPK signaling in transfected cells and in the striatum, which did not occur in cells expressing D 4.7 or in the striatum of knockin mutant mice carrying the 7 repeats of the human D 4.7 in the third intracellular loop of the D 4 receptor. In the striatum, D 4 receptors are localized in corticostriatal glutamatergic terminals, where they selectively modulate glutamatergic neurotransmission by interacting with D 2S receptors. This interaction shows the same qualitative characteristics than the D 2S-D 4 receptor heteromer-mediated mitogen-activated protein kinase (MAPK) signaling and D 2S receptor activation potentiates D 4 receptor-mediated inhibition of striatal glutamate release. It is therefore postulated that dysfunctional D 2S-D 4.7 heteromers may impair presynaptic dopaminergic control of corticostriatal glutamatergic neurotransmission and explain functional deficits associated with ADHD.
Fil: González, S.. Universidad de Barcelona; España
Fil: Rangel Barajas, C.. Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional; México
Fil: Peper, Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Lorenzo Lopez, Juan Ramiro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Moreno, E.. Universidad de Barcelona; España
Fil: Ciruela, F.. Universidad de Barcelona; España
Fil: Borycz, J.. National Institutes of Health; Estados Unidos
Fil: Ortiz, J.. Universitat Autònoma de Barcelona; España
Fil: Lluís, C.. Universidad de Barcelona; España
Fil: Franco, R.. Universidad de Navarra; España
Fil: McCormick, P. J.. Universidad de Barcelona; España
Fil: Volkow, N. D.. National Institutes of Health; Estados Unidos
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: Floran, B.. Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional; México
Fil: Ferré, S.. Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional; México
description Polymorphic variants of the dopamine D 4 receptor have been consistently associated with attention-deficit hyperactivity disorder (ADHD). However, the functional significance of the risk polymorphism (variable number of tandem repeats in exon 3) is still unclear. Here, we show that whereas the most frequent 4-repeat (D 4.4) and the 2-repeat (D 4.2) variants form functional heteromers with the short isoform of the dopamine D 2 receptor (D 2S), the 7-repeat risk allele (D 4.7) does not. D 2 receptor activation in the D 2S-D 4 receptor heteromer potentiates D 4 receptor-mediated MAPK signaling in transfected cells and in the striatum, which did not occur in cells expressing D 4.7 or in the striatum of knockin mutant mice carrying the 7 repeats of the human D 4.7 in the third intracellular loop of the D 4 receptor. In the striatum, D 4 receptors are localized in corticostriatal glutamatergic terminals, where they selectively modulate glutamatergic neurotransmission by interacting with D 2S receptors. This interaction shows the same qualitative characteristics than the D 2S-D 4 receptor heteromer-mediated mitogen-activated protein kinase (MAPK) signaling and D 2S receptor activation potentiates D 4 receptor-mediated inhibition of striatal glutamate release. It is therefore postulated that dysfunctional D 2S-D 4.7 heteromers may impair presynaptic dopaminergic control of corticostriatal glutamatergic neurotransmission and explain functional deficits associated with ADHD.
publishDate 2012
dc.date.none.fl_str_mv 2012-06
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/11336/79394
González, S.; Rangel Barajas, C.; Peper, Marcela; Lorenzo Lopez, Juan Ramiro; Moreno, E.; et al.; Dopamine D 4 receptor, but not the ADHD-associated D 4.7 variant, forms functional heteromers with the dopamine D 2S receptor in the brain; Nature Publishing Group; Molecular Psychiatry; 17; 6; 6-2012; 650-662
1359-4184
CONICET Digital
CONICET
url http://hdl.handle.net/11336/79394
identifier_str_mv González, S.; Rangel Barajas, C.; Peper, Marcela; Lorenzo Lopez, Juan Ramiro; Moreno, E.; et al.; Dopamine D 4 receptor, but not the ADHD-associated D 4.7 variant, forms functional heteromers with the dopamine D 2S receptor in the brain; Nature Publishing Group; Molecular Psychiatry; 17; 6; 6-2012; 650-662
1359-4184
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/mp201193
info:eu-repo/semantics/altIdentifier/url/https://pubmed.ncbi.nlm.nih.gov/21844870/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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reponame_str CONICET Digital (CONICET)
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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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