The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2024-03-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s44321-024-00054-w |
| _version_ | 1797199257395003392 |
|---|---|
| author | Carlos Costas-Insua Alba Hermoso-López Estefanía Moreno Carlos Montero-Fernández Alicia Álvaro-Blázquez Irene B Maroto Andrea Sánchez-Ruiz Rebeca Diez-Alarcia Cristina Blázquez Paula Morales Enric I Canela Vicent Casadó Leyre Urigüen Gertrudis Perea Luigi Bellocchio Ignacio Rodríguez-Crespo Manuel Guzmán |
| author_facet | Carlos Costas-Insua Alba Hermoso-López Estefanía Moreno Carlos Montero-Fernández Alicia Álvaro-Blázquez Irene B Maroto Andrea Sánchez-Ruiz Rebeca Diez-Alarcia Cristina Blázquez Paula Morales Enric I Canela Vicent Casadó Leyre Urigüen Gertrudis Perea Luigi Bellocchio Ignacio Rodríguez-Crespo Manuel Guzmán |
| author_sort | Carlos Costas-Insua |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-24T07:12:53Z |
| format | Article |
| id | doaj.art-5c7b69f9446144719e20ce1f4a631547 |
| institution | Directory Open Access Journal |
| issn | 1757-4684 |
| language | English |
| last_indexed | 2024-04-24T07:12:53Z |
| publishDate | 2024-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-5c7b69f9446144719e20ce1f4a6315472024-04-21T11:26:47ZengSpringer NatureEMBO Molecular Medicine1757-46842024-03-0116475578310.1038/s44321-024-00054-wThe CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfallsCarlos Costas-Insua0Alba Hermoso-López1Estefanía Moreno2Carlos Montero-Fernández3Alicia Álvaro-Blázquez4Irene B Maroto5Andrea Sánchez-Ruiz6Rebeca Diez-Alarcia7Cristina Blázquez8Paula Morales9Enric I Canela10Vicent Casadó11Leyre Urigüen12Gertrudis Perea13Luigi Bellocchio14Ignacio Rodríguez-Crespo15Manuel Guzmán16Department of Biochemistry and Molecular Biology, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense UniversityDepartment of Biochemistry and Molecular Biology, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense UniversityDepartment of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine of the University of Barcelona, University of BarcelonaDepartment of Biochemistry and Molecular Biology, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense UniversityDepartment of Biochemistry and Molecular Biology, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense UniversityDepartment of Biochemistry and Molecular Biology, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense UniversityCajal Institute, CSICDepartment of Pharmacology, University of the Basque Country/Euskal Herriko UnibertsitateaDepartment of Biochemistry and Molecular Biology, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense UniversityInstituto de Química Médica, CSICDepartment of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine of the University of Barcelona, University of BarcelonaDepartment of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine of the University of Barcelona, University of BarcelonaDepartment of Pharmacology, University of the Basque Country/Euskal Herriko UnibertsitateaCajal Institute, CSICInstitut National de la Santé et de la Recherche Médicale (INSERM) and University of Bordeaux, NeuroCentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215Department of Biochemistry and Molecular Biology, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense UniversityDepartment of Biochemistry and Molecular Biology, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense UniversityAbstract 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.https://doi.org/10.1038/s44321-024-00054-wCannabinoidCereblonHippocampusMemoryRimonabant |
| spellingShingle | Carlos Costas-Insua Alba Hermoso-López Estefanía Moreno Carlos Montero-Fernández Alicia Álvaro-Blázquez Irene B Maroto Andrea Sánchez-Ruiz Rebeca Diez-Alarcia Cristina Blázquez Paula Morales Enric I Canela Vicent Casadó Leyre Urigüen Gertrudis Perea Luigi Bellocchio Ignacio Rodríguez-Crespo Manuel Guzmán The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls EMBO Molecular Medicine Cannabinoid Cereblon Hippocampus Memory Rimonabant |
| title | The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls |
| title_full | The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls |
| title_fullStr | The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls |
| title_full_unstemmed | The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls |
| title_short | The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls |
| title_sort | cb1 receptor interacts with cereblon and drives cereblon deficiency associated memory shortfalls |
| topic | Cannabinoid Cereblon Hippocampus Memory Rimonabant |
| url | https://doi.org/10.1038/s44321-024-00054-w |
| work_keys_str_mv | AT carloscostasinsua thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT albahermosolopez thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT estefaniamoreno thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT carlosmonterofernandez thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT aliciaalvaroblazquez thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT irenebmaroto thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT andreasanchezruiz thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT rebecadiezalarcia thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT cristinablazquez thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT paulamorales thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT enricicanela thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT vicentcasado thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT leyreuriguen thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT gertrudisperea thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT luigibellocchio thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT ignaciorodriguezcrespo thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT manuelguzman thecb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT carloscostasinsua cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT albahermosolopez cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT estefaniamoreno cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT carlosmonterofernandez cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT aliciaalvaroblazquez cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT irenebmaroto cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT andreasanchezruiz cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT rebecadiezalarcia cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT cristinablazquez cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT paulamorales cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT enricicanela cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT vicentcasado cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT leyreuriguen cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT gertrudisperea cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT luigibellocchio cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT ignaciorodriguezcrespo cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls AT manuelguzman cb1receptorinteractswithcereblonanddrivescereblondeficiencyassociatedmemoryshortfalls |