title: Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1Receptor Heteromers in the Dorsal Striatum.
abstract: 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 A2Areceptor (A2AR) and cannabinoid CB1receptor (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.
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.|Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Moreno
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.|Instituto Universitario de Investigación Neuroquímica and Department of Biochemistry and Molecular Biology I, Complutense University, Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Chiarlone
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.|Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Medrano
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, UK.
authors.forename: Mar
authors.initials: M
authors.lastname: Puigdellívol
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, UK.
authors.forename: Lucka
authors.initials: L
authors.lastname: Bibic
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, UK.|School of Biological and Chemical Sciences, Queen Mary, University of London, London, UK.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Howell
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.|Instituto Universitario de Investigación Neuroquímica and Department of Biochemistry and Molecular Biology I, Complutense University, Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Resel
authors.affiliation: Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa, Spain.|Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.
authors.forename: Nagore
authors.initials: N
authors.lastname: Puente
authors.affiliation: Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Casarejos
authors.affiliation: Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Perucho
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, UK.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Botta
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.|Biomedical Science Department, School of Medicine; Institut d'Investigacions Biomèdiques August Pi i Sunyer, and Neuroscience Institute, Barcelona University, Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Suelves
authors.affiliation: Pharmacology Unit, Department of Pathology and Experimental Therapeutics, IDIBELL, and Neuroscience Institute, Barcelona University, Barcelona, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.|Biomedical Science Department, School of Medicine; Institut d'Investigacions Biomèdiques August Pi i Sunyer, and Neuroscience Institute, Barcelona University, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ginés
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.|Instituto Universitario de Investigación Neuroquímica and Department of Biochemistry and Molecular Biology I, Complutense University, Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors.forename: Ismael
authors.initials: I
authors.lastname: Galve-Roperh
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.|Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Vicent
authors.initials: V
authors.lastname: Casadó
authors.affiliation: Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa, Spain.|Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Grandes
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Monory
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.|Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Enric I
authors.identifier: 0000-0003-4992-7440
authors.initials: EI
authors.lastname: Canela
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.|Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Lluís
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.|Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.|School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, UK.|Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McCormick
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.|Instituto Universitario de Investigación Neuroquímica and Department of Biochemistry and Molecular Biology I, Complutense University, Madrid, Spain.|Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzmán
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism; D051379:Mice; D009434:Neural Pathways / Q000378:metabolism; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000096:biosynthesis; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D021122:Protein Subunits; D043705:Receptor, Adenosine A2A; D043884:Receptor, Cannabinoid, CB1