Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum

The dorsal striatum is a key node for many neurobiological processes such as motor activity, cognitive functions, and affective processes. The proper functioning of striatal neurons relies critically on metabotropic receptors. Specifically, the main adenosine and endocannabinoid receptors present in...

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Autores: Moreno Guillén, Estefanía, Chiarlone, Anna, Medrano Moya, Mireia, Puigdellívol Cañadell, Maria del Mar, Bibic, Lucka, Howell, Lesley A., Resel, Eva, Puente, Nagore, Casarejos, María J., Perucho, Juan, Botta, Joaquín, Suelves Caballol, Núria, Ciruela Alférez, Francisco, Ginés Padrós, Silvia, Galve-Roperh, Ismael, Casadó, Vicent, Grandes, P, Lutz, Beat, Monory, Krisztina, Canela Campos, Enric I. (Enric Isidre), 1949-, Lluís i Biset, Carme, McCormick, Peter J., Guzmán, Manuel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/172761
Acceso en línea:https://hdl.handle.net/2445/172761
Access Level:acceso abierto
Palabra clave:Adenosina
Neurobiologia
Adenosine
Neurobiology
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spelling Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal StriatumMoreno Guillén, EstefaníaChiarlone, AnnaMedrano Moya, MireiaPuigdellívol Cañadell, Maria del MarBibic, LuckaHowell, Lesley A.Resel, EvaPuente, NagoreCasarejos, María J.Perucho, JuanBotta, JoaquínSuelves Caballol, NúriaCiruela Alférez, FranciscoGinés Padrós, SilviaGalve-Roperh, IsmaelCasadó, VicentGrandes, PLutz, BeatMonory, KrisztinaCanela Campos, Enric I. (Enric Isidre), 1949-Lluís i Biset, CarmeMcCormick, Peter J.Guzmán, ManuelAdenosinaNeurobiologiaAdenosineNeurobiologyThe dorsal striatum is a key node for many neurobiological processes such as motor activity, cognitive functions, and affective processes. The proper functioning of striatal neurons relies critically on metabotropic receptors. Specifically, the main adenosine and endocannabinoid receptors present in the striatum, ie, adenosine A2A receptor (A2AR) and cannabinoid CB1 receptor (CB1R), are of pivotal importance in the control of neuronal excitability. Facilitatory and inhibitory functional interactions between striatal A2AR and CB1R have been reported, and evidence supports that this cross-talk may rely, at least in part, on the formation of A2AR-CB1R heteromeric complexes. However, the specific location and properties of these heteromers have remained largely unknown. Here, by using techniques that allowed a precise visualization of the heteromers in situ in combination with sophisticated genetically modified animal models, together with biochemical and pharmacological approaches, we provide a high-resolution expression map and a detailed functional characterization of A2AR-CB1R heteromers in the dorsal striatum. Specifically, our data unveil that the A2AR-CB1R heteromer (i) is essentially absent from corticostriatal projections and striatonigral neurons, and, instead, is largely present in striatopallidal neurons, (ii) displays a striking G protein-coupled signaling profile, where co-stimulation of both receptors leads to strongly reduced downstream signaling, and (iii) undergoes an unprecedented dysfunction in Huntington's disease, an archetypal disease that affects striatal neurons. Altogether, our findings may open a new conceptual framework to understand the role of coordinated adenosine-endocannabinoid signaling in the indirect striatal pathway, which may be relevant in motor function and neurodegenerative diseases.Nature Publishing Group2020202020182020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion14 p.application/pdfhttps://hdl.handle.net/2445/172761Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1038/npp.2017.12Neuropsychopharmacology, 2018, vol. 43, num. 5, p. 964-977https://doi.org/10.1038/npp.2017.12cc by (c) Moreno Guillén et al., 2018http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1727612026-05-29T05:05:01Z
dc.title.none.fl_str_mv Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum
title Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum
spellingShingle Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum
Moreno Guillén, Estefanía
Adenosina
Neurobiologia
Adenosine
Neurobiology
title_short Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum
title_full Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum
title_fullStr Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum
title_full_unstemmed Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum
title_sort Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum
dc.creator.none.fl_str_mv Moreno Guillén, Estefanía
Chiarlone, Anna
Medrano Moya, Mireia
Puigdellívol Cañadell, Maria del Mar
Bibic, Lucka
Howell, Lesley A.
Resel, Eva
Puente, Nagore
Casarejos, María J.
Perucho, Juan
Botta, Joaquín
Suelves Caballol, Núria
Ciruela Alférez, Francisco
Ginés Padrós, Silvia
Galve-Roperh, Ismael
Casadó, Vicent
Grandes, P
Lutz, Beat
Monory, Krisztina
Canela Campos, Enric I. (Enric Isidre), 1949-
Lluís i Biset, Carme
McCormick, Peter J.
Guzmán, Manuel
author Moreno Guillén, Estefanía
author_facet Moreno Guillén, Estefanía
Chiarlone, Anna
Medrano Moya, Mireia
Puigdellívol Cañadell, Maria del Mar
Bibic, Lucka
Howell, Lesley A.
Resel, Eva
Puente, Nagore
Casarejos, María J.
Perucho, Juan
Botta, Joaquín
Suelves Caballol, Núria
Ciruela Alférez, Francisco
Ginés Padrós, Silvia
Galve-Roperh, Ismael
Casadó, Vicent
Grandes, P
Lutz, Beat
Monory, Krisztina
Canela Campos, Enric I. (Enric Isidre), 1949-
Lluís i Biset, Carme
McCormick, Peter J.
Guzmán, Manuel
author_role author
author2 Chiarlone, Anna
Medrano Moya, Mireia
Puigdellívol Cañadell, Maria del Mar
Bibic, Lucka
Howell, Lesley A.
Resel, Eva
Puente, Nagore
Casarejos, María J.
Perucho, Juan
Botta, Joaquín
Suelves Caballol, Núria
Ciruela Alférez, Francisco
Ginés Padrós, Silvia
Galve-Roperh, Ismael
Casadó, Vicent
Grandes, P
Lutz, Beat
Monory, Krisztina
Canela Campos, Enric I. (Enric Isidre), 1949-
Lluís i Biset, Carme
McCormick, Peter J.
Guzmán, Manuel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Adenosina
Neurobiologia
Adenosine
Neurobiology
topic Adenosina
Neurobiologia
Adenosine
Neurobiology
description The dorsal striatum is a key node for many neurobiological processes such as motor activity, cognitive functions, and affective processes. The proper functioning of striatal neurons relies critically on metabotropic receptors. Specifically, the main adenosine and endocannabinoid receptors present in the striatum, ie, adenosine A2A receptor (A2AR) and cannabinoid CB1 receptor (CB1R), are of pivotal importance in the control of neuronal excitability. Facilitatory and inhibitory functional interactions between striatal A2AR and CB1R have been reported, and evidence supports that this cross-talk may rely, at least in part, on the formation of A2AR-CB1R heteromeric complexes. However, the specific location and properties of these heteromers have remained largely unknown. Here, by using techniques that allowed a precise visualization of the heteromers in situ in combination with sophisticated genetically modified animal models, together with biochemical and pharmacological approaches, we provide a high-resolution expression map and a detailed functional characterization of A2AR-CB1R heteromers in the dorsal striatum. Specifically, our data unveil that the A2AR-CB1R heteromer (i) is essentially absent from corticostriatal projections and striatonigral neurons, and, instead, is largely present in striatopallidal neurons, (ii) displays a striking G protein-coupled signaling profile, where co-stimulation of both receptors leads to strongly reduced downstream signaling, and (iii) undergoes an unprecedented dysfunction in Huntington's disease, an archetypal disease that affects striatal neurons. Altogether, our findings may open a new conceptual framework to understand the role of coordinated adenosine-endocannabinoid signaling in the indirect striatal pathway, which may be relevant in motor function and neurodegenerative diseases.
publishDate 2018
dc.date.none.fl_str_mv 2018
2020
2020
2020
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://hdl.handle.net/2445/172761
url https://hdl.handle.net/2445/172761
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/npp.2017.12
Neuropsychopharmacology, 2018, vol. 43, num. 5, p. 964-977
https://doi.org/10.1038/npp.2017.12
dc.rights.none.fl_str_mv cc by (c) Moreno Guillén et al., 2018
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Moreno Guillén et al., 2018
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 14 p.
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 Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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