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Title: Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum
Author: Moreno Guillén, Estefanía
Chiarlone, Anna
Medrano Moya, Mireia
Puigdellívol Cañadell, Maria del Mar
Bibic, Lucka
Howell, Lesley A.
Resel, Eva
Puente, Nagore
Casarejos, María J.
Perucho, Juan
Botta, Joaquín
Suelves, Nuria
Ciruela Alférez, Francisco
Ginés Padrós, Silvia
Galve-Roperh, Ismael
Casadó, Vicent
Grandes, P
Lutz, Beat
Monory, Krisztina
Canela Campos, Enric I.
Lluís i Biset, Carme
McCormick, Peter J.
Guzmán, Manuel
Keywords: Adenosina
Issue Date: Jan-2018
Publisher: Nature Publishing Group
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 A2A receptor (A2AR) and cannabinoid CB1 receptor (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.
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It is part of: Neuropsychopharmacology, 2018, vol. 43, num. 5, p. 964-977
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ISSN: 0893-133X
Appears in Collections:Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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