The CB 1 receptor interacts with cereblon and drivescereblon deficiency-associated memory shortfalls

Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reductio...

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Autores: Costas Insua, Carlos, Hermoso López, Alba, Moreno, Estefanía, Montero Fernández, Carlos, Álvaro Blázquez, Alicia, Maroto, Irene B., Sánchez Ruiz, Andrea, Díez Alarcia, Rebeca, Blázquez Ortiz, Cristina, Morales, Paula, Canela, Enric I., Casadó, Vicent, Urigüen Echeverría, Leyre, Perea, Gertrudis, Bellochio, Luigi, Rodríguez Crespo, Ignacio, Guzmán, Manuel
Formato: artículo
Fecha de publicación:2024
País:España
Recursos:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/72045
Acesso em linha:http://hdl.handle.net/10810/72045
Access Level:acceso abierto
Palavra-chave:cannabinoid
cereblon
hippocampus
memory
rimonabant
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oai_identifier_str oai:addi.ehu.eus:10810/72045
network_acronym_str ES
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repository_id_str
spelling The CB 1 receptor interacts with cereblon and drivescereblon deficiency-associated memory shortfallsCostas Insua, CarlosHermoso López, AlbaMoreno, EstefaníaMontero Fernández, CarlosÁlvaro Blázquez, AliciaMaroto, Irene B.Sánchez Ruiz, AndreaDíez Alarcia, RebecaBlázquez Ortiz, CristinaMorales, PaulaCanela, Enric I.Casadó, VicentUrigüen Echeverría, LeyrePerea, GertrudisBellochio, LuigiRodríguez Crespo, IgnacioGuzmán, ManuelcannabinoidcereblonhippocampusmemoryrimonabantCereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reduction in excitatory neurotransmission has been proposed as an underlying mechanism of the disease. However, the precise factors eliciting this impairment remain mostly unknown. Here we report that CRBN molecules selectively located on glutamatergic neurons are necessary for proper memory function. Combining various in vivo approaches, we show that the cannabinoid CB1 receptor (CB1R), a key suppressor of synaptic transmission, is overactivated in CRBN deficiency-linked ARNSID mouse models, and that the memory deficits observed in these animals can be rescued by acute CB1R-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CB1R and impairs the CB1R-Gi/o-cAMP-PKA pathway in a ubiquitin ligase-independent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.EMBO Press202520252024info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/72045reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoIngléshttps://www.embopress.org/doi/full/10.1038/s44321-024-00054-winfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/© 2024 The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International Licenseoai:addi.ehu.eus:10810/720452026-06-18T09:23:17Z
dc.title.none.fl_str_mv The CB 1 receptor interacts with cereblon and drivescereblon deficiency-associated memory shortfalls
title The CB 1 receptor interacts with cereblon and drivescereblon deficiency-associated memory shortfalls
spellingShingle The CB 1 receptor interacts with cereblon and drivescereblon deficiency-associated memory shortfalls
Costas Insua, Carlos
cannabinoid
cereblon
hippocampus
memory
rimonabant
title_short The CB 1 receptor interacts with cereblon and drivescereblon deficiency-associated memory shortfalls
title_full The CB 1 receptor interacts with cereblon and drivescereblon deficiency-associated memory shortfalls
title_fullStr The CB 1 receptor interacts with cereblon and drivescereblon deficiency-associated memory shortfalls
title_full_unstemmed The CB 1 receptor interacts with cereblon and drivescereblon deficiency-associated memory shortfalls
title_sort The CB 1 receptor interacts with cereblon and drivescereblon deficiency-associated memory shortfalls
dc.creator.none.fl_str_mv Costas Insua, Carlos
Hermoso López, Alba
Moreno, Estefanía
Montero Fernández, Carlos
Álvaro Blázquez, Alicia
Maroto, Irene B.
Sánchez Ruiz, Andrea
Díez Alarcia, Rebeca
Blázquez Ortiz, Cristina
Morales, Paula
Canela, Enric I.
Casadó, Vicent
Urigüen Echeverría, Leyre
Perea, Gertrudis
Bellochio, Luigi
Rodríguez Crespo, Ignacio
Guzmán, Manuel
author Costas Insua, Carlos
author_facet Costas Insua, Carlos
Hermoso López, Alba
Moreno, Estefanía
Montero Fernández, Carlos
Álvaro Blázquez, Alicia
Maroto, Irene B.
Sánchez Ruiz, Andrea
Díez Alarcia, Rebeca
Blázquez Ortiz, Cristina
Morales, Paula
Canela, Enric I.
Casadó, Vicent
Urigüen Echeverría, Leyre
Perea, Gertrudis
Bellochio, Luigi
Rodríguez Crespo, Ignacio
Guzmán, Manuel
author_role author
author2 Hermoso López, Alba
Moreno, Estefanía
Montero Fernández, Carlos
Álvaro Blázquez, Alicia
Maroto, Irene B.
Sánchez Ruiz, Andrea
Díez Alarcia, Rebeca
Blázquez Ortiz, Cristina
Morales, Paula
Canela, Enric I.
Casadó, Vicent
Urigüen Echeverría, Leyre
Perea, Gertrudis
Bellochio, Luigi
Rodríguez Crespo, Ignacio
Guzmán, Manuel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv cannabinoid
cereblon
hippocampus
memory
rimonabant
topic cannabinoid
cereblon
hippocampus
memory
rimonabant
description Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reduction in excitatory neurotransmission has been proposed as an underlying mechanism of the disease. However, the precise factors eliciting this impairment remain mostly unknown. Here we report that CRBN molecules selectively located on glutamatergic neurons are necessary for proper memory function. Combining various in vivo approaches, we show that the cannabinoid CB1 receptor (CB1R), a key suppressor of synaptic transmission, is overactivated in CRBN deficiency-linked ARNSID mouse models, and that the memory deficits observed in these animals can be rescued by acute CB1R-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CB1R and impairs the CB1R-Gi/o-cAMP-PKA pathway in a ubiquitin ligase-independent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/72045
url http://hdl.handle.net/10810/72045
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://www.embopress.org/doi/full/10.1038/s44321-024-00054-w
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv EMBO Press
publisher.none.fl_str_mv EMBO Press
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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