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, Estefanía, Chiarlone, Anna, Medrano, Mireia, Puigdellivol, Mar, Bibic, Lucka, Howell, Lesley A., Resel, Eva, Puente Bustinza, Nagore, Casarejos, Maria J., Perucho, Juan, Botta, Joaquín, Suelves, Nuria, Ciruela, Francisco, Ginés, Silvia, Galve Roperh, Ismael, Casadó, Vicent, Grandes Moreno, Pedro Rolando, Lutz, Beat, Monory, Krisztina, Canela, Enric I., Lluis, Carmen, McCormick, Peter J., Guzmán, Manuel
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/30726
Acceso en línea:http://hdl.handle.net/10810/30726
Access Level:acceso abierto
Palabra clave:protein-coupled receptors
huntingtons-disease mice
transgenic mouse model
A(2A) receptors
cannabinoid CB1
basal ganglia
glutamatergic neurotransmission
allosteric interactions
endocannabinoid system
mediated inhibition
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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, Estefanía
protein-coupled receptors
huntingtons-disease mice
transgenic mouse model
A(2A) receptors
cannabinoid CB1
basal ganglia
glutamatergic neurotransmission
allosteric interactions
endocannabinoid system
mediated inhibition
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, Estefanía
Chiarlone, Anna
Medrano, Mireia
Puigdellivol, Mar
Bibic, Lucka
Howell, Lesley A.
Resel, Eva
Puente Bustinza, Nagore
Casarejos, Maria J.
Perucho, Juan
Botta, Joaquín
Suelves, Nuria
Ciruela, Francisco
Ginés, Silvia
Galve Roperh, Ismael
Casadó, Vicent
Grandes Moreno, Pedro Rolando
Lutz, Beat
Monory, Krisztina
Canela, Enric I.
Lluis, Carmen
McCormick, Peter J.
Guzmán, Manuel
author Moreno, Estefanía
author_facet Moreno, Estefanía
Chiarlone, Anna
Medrano, Mireia
Puigdellivol, Mar
Bibic, Lucka
Howell, Lesley A.
Resel, Eva
Puente Bustinza, Nagore
Casarejos, Maria J.
Perucho, Juan
Botta, Joaquín
Suelves, Nuria
Ciruela, Francisco
Ginés, Silvia
Galve Roperh, Ismael
Casadó, Vicent
Grandes Moreno, Pedro Rolando
Lutz, Beat
Monory, Krisztina
Canela, Enric I.
Lluis, Carmen
McCormick, Peter J.
Guzmán, Manuel
author_role author
author2 Chiarlone, Anna
Medrano, Mireia
Puigdellivol, Mar
Bibic, Lucka
Howell, Lesley A.
Resel, Eva
Puente Bustinza, Nagore
Casarejos, Maria J.
Perucho, Juan
Botta, Joaquín
Suelves, Nuria
Ciruela, Francisco
Ginés, Silvia
Galve Roperh, Ismael
Casadó, Vicent
Grandes Moreno, Pedro Rolando
Lutz, Beat
Monory, Krisztina
Canela, Enric I.
Lluis, Carmen
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 protein-coupled receptors
huntingtons-disease mice
transgenic mouse model
A(2A) receptors
cannabinoid CB1
basal ganglia
glutamatergic neurotransmission
allosteric interactions
endocannabinoid system
mediated inhibition
topic protein-coupled receptors
huntingtons-disease mice
transgenic mouse model
A(2A) receptors
cannabinoid CB1
basal ganglia
glutamatergic neurotransmission
allosteric interactions
endocannabinoid system
mediated inhibition
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 A(2A) receptor (A(2A)R) and cannabinoid CB1 receptor (CB1R), are of pivotal importance in the control of neuronal excitability. Facilitatory and inhibitory functional interactions between striatal A(2A)R and CB1R have been reported, and evidence supports that this cross-talk may rely, at least in part, on the formation of A(2A)R-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 A(2A)R-CB1R heteromers in the dorsal striatum. Specifically, our data unveil that the A(2A)R-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
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/30726
url http://hdl.handle.net/10810/30726
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MINECO/SAF2015-64945-R/
info:eu-repo/grantAgreement/MINECO/ SAF-2014-54840-R/
info:eu-repo/grantAgreement/MINECO/SAF2015-65034-R/
info:eu-repo/grantAgreement/MINECO/SAF2015-67474-R/
info:eu-repo/grantAgreement/MINECO/SAF2014-55700-P/
info:eu-repo/grantAgreement/MINECO/PCIN-2013-019-C03-03/
info:eu-repo/grantAgreement/MINECO/PIE14/00034
info:eu-repo/grantAgreement/MINECO/PI10/00172
https://www.nature.com/articles/npp201712
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/3.0/es/
http://creativecommons.org/licenses/by/4.0/
Atribución 3.0 España
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/3.0/es/
http://creativecommons.org/licenses/by/4.0/
Atribución 3.0 España
dc.format.none.fl_str_mv 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: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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spelling Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal StriatumMoreno, EstefaníaChiarlone, AnnaMedrano, MireiaPuigdellivol, MarBibic, LuckaHowell, Lesley A.Resel, EvaPuente Bustinza, NagoreCasarejos, Maria J.Perucho, JuanBotta, JoaquínSuelves, NuriaCiruela, FranciscoGinés, SilviaGalve Roperh, IsmaelCasadó, VicentGrandes Moreno, Pedro RolandoLutz, BeatMonory, KrisztinaCanela, Enric I.Lluis, CarmenMcCormick, Peter J.Guzmán, Manuelprotein-coupled receptorshuntingtons-disease micetransgenic mouse modelA(2A) receptorscannabinoid CB1basal gangliaglutamatergic neurotransmissionallosteric interactionsendocannabinoid systemmediated inhibitionThe 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 A(2A) receptor (A(2A)R) and cannabinoid CB1 receptor (CB1R), are of pivotal importance in the control of neuronal excitability. Facilitatory and inhibitory functional interactions between striatal A(2A)R and CB1R have been reported, and evidence supports that this cross-talk may rely, at least in part, on the formation of A(2A)R-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 A(2A)R-CB1R heteromers in the dorsal striatum. Specifically, our data unveil that the A(2A)R-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.This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO/FEDER; grant SAF2015-64945-R to MG; grant SAF-2014-54840-R to EIC and VC; grant SAF2015-65034-R to PG; grant SAF2015-67474-R to SG; grants SAF2014-55700-P and PCIN-2013-019-C03-03 to FC); Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED; grant PI2013/05 to MG, PJM and EIC); Comunidad de Madrid (grant S2010/BMD-2308 to MG); Generalitat de Catalunya (grant 2014-SGR-1236 to EIC); 'La Marato de TV3' Foundation (grant 20140610 to EIC; grant 20152031 to FC); Agentschap voor Innovatie door Wetenschap en Technologie (grant SBO-140028 to FC); BBSRC DTP studentship (to PJM and LB); EPSRC (grant EP/M006379/1 to LAH); Deutsche Forschungsgemeinschaft (DFG; grant MO 1920/1-1 to KM; grant CRC-TRR 58 to BL); Institute of Health Carlos III from the Spanish Ministry of Economy and Competitiveness (grant PIE14/00034 to FC; grant PI10/00172 and funding from FEDER grants to MJC and JP); The Basque Government (grant IT764-13 to PG); University of the Basque Country UPV/EHU (grant UFI11/41 to PG); Red de Trastornos Adictivos-Institute of Health Carlos III (grant RD12/0028/0004 to PG). AC is supported by the Spanish Ministry of Economy and Competitiveness (Juan de la Cierva Program). MM is supported by the Spanish Ministry of Education, Culture and Sport (FPU Program). The authors declare no conflict of interest.Nature Publishing Group201920192018info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/30726reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/MINECO/SAF2015-64945-R/info:eu-repo/grantAgreement/MINECO/ SAF-2014-54840-R/info:eu-repo/grantAgreement/MINECO/SAF2015-65034-R/info:eu-repo/grantAgreement/MINECO/SAF2015-67474-R/info:eu-repo/grantAgreement/MINECO/SAF2014-55700-P/info:eu-repo/grantAgreement/MINECO/PCIN-2013-019-C03-03/info:eu-repo/grantAgreement/MINECO/PIE14/00034info:eu-repo/grantAgreement/MINECO/PI10/00172https://www.nature.com/articles/npp201712info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/http://creativecommons.org/licenses/by/4.0/Atribución 3.0 Españaoai:addi.ehu.eus:10810/307262026-06-18T09:23:17Z
score 15,300719

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