Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A2A-Dopamine D2 Receptor Heterotetramers and Adenylyl Cyclase

Abstract

The central adenosine system and adenosine receptors play a fundamental role in the modulation of dopaminergic neurotransmission. This is mostly achieved by the strategic co-localization of different adenosine and dopamine receptor subtypes in the two populations of striatal efferent neurons, striatonigral and striatopallidal, that give rise to the direct and indirect striatal efferent pathways, respectively. With optogenetic techniques it has been possible to dissect a differential role of the direct and indirect pathways in mediating “Go” responses upon exposure to reward-related stimuli and “NoGo” responses upon exposure to non-rewarded or aversive-related stimuli, respectively, which depends on their different connecting output structures and their differential expression of dopamine and adenosine receptor subtypes. The striatopallidal neuron selectively expresses dopamine D2 receptors (D2R) and adenosine A2A receptors (A2AR), and numerous experiments using multiple genetic and pharmacological in vitro, in situ and in vivo approaches, demonstrate they can form A2AR-D2R heteromers. It was initially assumed that different pharmacological interactions between dopamine and adenosine receptor ligands indicated the existence of different subpopulations of A2AR and D2R in the striatopallidal neuron. However, as elaborated in the present essay, most evidence now indicates that all interactions can be explained with a predominant population of striatal A2AR-D2R heteromers forming complexes with adenylyl cyclase subtype 5 (AC5). The A2AR-D2R heteromer has a tetrameric structure, with two homodimers, which allows not only multiple allosteric interactions between different orthosteric ligands, agonists, and antagonists, but also the canonical Gs-Gi antagonistic interaction at the level of AC5. We present a model of the function of the A2AR-D2R heterotetramer-AC5 complex, which acts as an integrative device of adenosine and dopamine signals that determine the excitability and gene expression of the striatopallidal neurons. The model can explain most behavioral effects of A2AR and D2R ligands, including the psychostimulant effects of caffeine. The model is also discussed in the context of different functional striatal compartments, mainly the dorsal and the ventral striatum. The current accumulated knowledge of the biochemical properties of the A2AR-D2R heterotetramer-AC5 complex offers new therapeutic possibilities for Parkinson’s disease, schizophrenia, SUD and other neuropsychiatric disorders with dysfunction of dorsal or ventral striatopallidal neurons.

Striatal Dopamine D2-Muscarinic Acetylcholine M1 Receptor–Receptor Interaction in a Model of Movement Disorders

“…In the last years, G protein-couped receptor (GPCR) oligomers have gained interest as novel putative targets for several diseases. One of the most well-characterized D 2 R-containing oligomers is the D 2 R/A 2A R heteromer in the striatum, where reciprocal antagonistic interactions both at the binding and effector levels occur between these receptors (Ferré et al, 2018). Importantly, this functional interplay grounded the utility of A 2A R blockade in PD treatment, which recently ended with the approval of a selective A 2A R antagonist, istradefylline (Nourianz), as an adjuvant drug in PD treatment.…”

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

“…Postsynaptic A 2A R, differently from presynaptic A 2A R, are therefore tonically activated, which produces significant behavioral and biochemical effects that can be disclosed when A 2A R is blocked after the administration of an antagonist (see below). 142 Adenosine receptor single nucleotide polymorphisms and caffeine intake…”

A Dual Role Hypothesis of the Cortico-Basal-Ganglia Pathways: Opponency and Temporal Difference through Dopamine and Adenosine

“…2B). In contrast, at IT→iMSN synapses where adenosine is scarce, phasic DA representing positive RPE is expected to cause LTD via D2R signaling, which could then inhibit A2A receptor signaling through the suggested canonical antagonistic interaction at the level of adenylyl cyclase (Kull et al, 1999;Hillion et al, 2002;Navarro et al, 2014;Ferré et al, 2018). Figure 2A shows the integrated Opponency & Temporal-Difference (OTD) model.…”

“…Since experimental validation would not be straightforward, it would be desired to first construct mathematical models, based on previous models of the signaling cascades in MSNs (Lindskog et al, 2006;Nakano et al, 2010;Nair et al, 2015). Known properties of adenosine (Schiffmann et al, 2007;Wall and Dale, 2008;Ferré et al, 2018), time course of phasic DA release (Day et al, 2007;Yagishita et al, 2014;Nair et al, 2016), and also dendritic morphology (Lindroos et al, 2018) and spines (Blackwell et al, 2018) are desired to be incorporated.…”