Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum

Moreno, E, Chiarlone, A, Medrano, M, Puigdellívol, M, Bibic, L, Howell, LA, Resel, E, Puente, N, Casarejos, MJ, Perucho, J et al, Botta, J, Suelves, N, Ciruela, F, Ginés, S, Galve-Roperh, I, Casadó, V, Grandes, P, Lutz, B, Monory, K, Canela, EI, Lluís, C, McCormick, Peter and Guzmán, M (2017) Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum Neuropsychopharmacology. pp. 1-14.

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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.

Item Type:	Article
Subjects :	Veterinary Medicine
Divisions :	Faculty of Health and Medical Sciences > School of Veterinary Medicine
Authors :	Name Email ORCID Moreno, E Chiarlone, A Medrano, M Puigdellívol, M Bibic, L Howell, LA Resel, E Puente, N Casarejos, MJ Perucho, J Botta, J Suelves, N Ciruela, F Ginés, S Galve-Roperh, I Casadó, V Grandes, P Lutz, B Monory, K Canela, EI Lluís, C McCormick, Peter p.mccormick@surrey.ac.uk Guzmán, M
Date :	15 February 2017
DOI :	10.1038/npp.2017.12
Copyright Disclaimer :	© The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the CreativeCommons license, userswill need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/ by/4.0/
Depositing User :	Symplectic Elements
Date Deposited :	03 Mar 2017 12:14
Last Modified :	16 Jan 2019 17:12
URI:	http://epubs.surrey.ac.uk/id/eprint/813685

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