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...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; |
|---|---|
| Format: | Article |
| Publication date: | 2018 |
| Country: | España |
| Institution: | Universidad del País Vasco |
| Repository: | Addi. Archivo Digital para la Docencia y la Investigación |
| OAI Identifier: | oai:addi.ehu.eus:10810/30726 |
| Online Access: | http://hdl.handle.net/10810/30726 |
| Access Level: | Open access |
| Keyword: | protein-coupled receptors huntingtons-disease mice transgenic mouse model A(2A) receptors cannabinoid CB1 basal ganglia glutamatergic neurotransmission allosteric interactions endocannabinoid system mediated inhibition |
| _version_ | 1878735485467099136 |
|---|---|
| author | Moreno, Estefanía |
| 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 |
| author_browse | Bibic, Lucka Botta, Joaquín Canela, Enric I. Casadó, Vicent Casarejos, Maria J. Chiarlone, Anna Ciruela, Francisco Galve Roperh, Ismael Ginés, Silvia Grandes Moreno, Pedro Rolando Guzmán, Manuel Howell, Lesley A. Lluis, Carmen Lutz, Beat McCormick, Peter J. Medrano, Mireia Monory, Krisztina Moreno, Estefanía Perucho, Juan Puente Bustinza, Nagore Puigdellivol, Mar Resel, Eva Suelves, Nuria |
| 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 |
| collection | Addi. Archivo Digital para la Docencia y la Investigación |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_7d9f4f2cd83d3697abf0da91fa84241d |
| institution | Universidad del País Vasco |
| instname_str | Universidad del País Vasco |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:addi.ehu.eus:10810/30726 |
| publishDate | 2018 |
| publishDateSort | 2018 |
| publisher | Nature Publishing Group |
| publisherStr | Nature Publishing Group |
| reponame_str | Addi. Archivo Digital para la Docencia y la Investigación |
| spelling | Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum 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 protein-coupled receptors huntingtons-disease mice transgenic mouse model A(2A) receptors cannabinoid CB1 basal ganglia glutamatergic neurotransmission allosteric interactions endocannabinoid system mediated inhibition 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. 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 Group http://hdl.handle.net/10810/30726 |
| 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 | 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_short | 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 |
| 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 |
| topic_facet | protein-coupled receptors huntingtons-disease mice transgenic mouse model A(2A) receptors cannabinoid CB1 basal ganglia glutamatergic neurotransmission allosteric interactions endocannabinoid system mediated inhibition |
| url | http://hdl.handle.net/10810/30726 |