Singular location and signaling profile of adenosine A2A-cannabinoid CB1 receptor heteromers in the dorsal striatum

Tools

Moreno, Estefanía, Chiarlone, Anna, Medrano, Mireia, Puigdellívol, Mar, Bibic, Lucka, Howell, Lesley A., Resel, Eva, Puente, Nagore, Casarejos, María J., Perucho, Juan, Botta, Joaquín, Suelves, Nuria, Ciruela, Francisco, Ginés, Silvia, Galve-Roperh, Ismael, Casadó, Vicent, Grandes, Pedro, Lutz, Beat, Monory, Krisztina, Canela, Enric I., Lluís, Carmen, McCormick, Peter J. and Guzmán, Manuel (2018) Singular location and signaling profile of adenosine A2A-cannabinoid CB1 receptor heteromers in the dorsal striatum. Neuropsychopharmacology, 43. 964–977. ISSN 0893-133X

[thumbnail of Accepted manuscript]
Preview
 PDF (Accepted manuscript) - Accepted Version
Available under License Creative Commons Attribution.
Download (2MB) | Preview

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
Faculty \ School: Faculty of Science > School of Pharmacy
Related URLs:
Depositing User: Pure Connector
Date Deposited: 02 Feb 2017 03:50
Last Modified: 21 Oct 2022 09:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/62281
DOI: 10.1038/npp.2017.12

Downloads

Downloads per month over past year

Actions (login required)

View Item View Item