Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor 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 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.

Endocannabinoid system in neurodegenerative disorders

“…The A 2A R‐CB1R form heteromeric complexes and recent studies revealed that the complex becomes dysfunctional in caudate putamen of advanced HD patients (Moreno et al . ).…”

“…Along with CB1R, adenosine A 2A receptor (A 2A R) plays an important role in the control of neuronal excitability. The A 2A R-CB1R form heteromeric complexes and recent studies revealed that the complex becomes dysfunctional in caudate putamen of advanced HD patients (Moreno et al 2017).…”

The adenosine A2A receptor agonist, CGS 21680, attenuates a probabilistic reversal learning deficit and elevated grooming behavior in BTBR mice

“…A 1 receptors are expressed ubiquitously in the brain while A 2A receptors are primarily expressed in the striatum and olfactory tubercle [Dunwiddie & Masino, 2001]. Further, A 2A receptors in the striatum are almost exclusively expressed postsynaptically in striato-pallidal neurons of the indirect pathway [Moreno et al, 2017]. It has been shown that stimulation of adenosine A 2A receptors can counteract the inhibitory effects of dopamine D 2 receptors on striatal indirect pathway neurons [Nair, Gutierrez-Arenas, Eriksson, Vincent, & Hellgren Kotaleski, 2015].…”

Papel do receptor B2 de cininas na terapia da neurodegeneração dopaminérgica em modelo animal

“…Neutrophils from HD patients have higher A 2A receptor dysfunction in homozygous vs. heterozygous HD patients while no changes in A 1 or A 3 receptors are observed in peripheral blood cells (Varani et al, 2003). A 2A -cannabinoid CB1 receptor heterodimers exert crucial function by controlling neuronal excitability (Moreno et al, 2017), while activation of striatal A 2A receptors may inhibit CB1 function independent from heterodimer formation (Ferreira et al, 2015). Patients harboring high-grade HD do not possess A 2A -CB1 receptor heterodimers in the caudate-putamen region due to the lack of CB1 receptors (Moreno et al, 2017).…”

“…A 2A -cannabinoid CB1 receptor heterodimers exert crucial function by controlling neuronal excitability (Moreno et al, 2017), while activation of striatal A 2A receptors may inhibit CB1 function independent from heterodimer formation (Ferreira et al, 2015). Patients harboring high-grade HD do not possess A 2A -CB1 receptor heterodimers in the caudate-putamen region due to the lack of CB1 receptors (Moreno et al, 2017). Recent evidence suggests that consuming more than 190 mg/day of caffeine may accelerate HD onset (Simonin et al, 2013), contradicting findings in animal models that point toward beneficial effects of A 2A receptor antagonism in HD.…”