Allosteric mechanisms within the adenosine A2A-dopamine D2 receptor heterotetramer

Abstract

The structure constituted by a G protein coupled receptor (GPCR) homodimer and a G protein provides a main functional unit and oligomeric entities can be viewed as multiples of dimers. For GPCR heteromers, experimental evidence supports a tetrameric structure, comprised of two different homodimers, each able to signal with its preferred G protein. GPCR homomers and heteromers can act as the conduit of allosteric interactions between orthosteric ligands. The well-known agonist/agonist allosteric interaction in the adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromer, by which A2AR agonists decrease the affinity of D2R agonists, gave the first rationale for the use of A2AR antagonists in Parkinson's disease. We review new pharmacological findings that can be explained in the frame of a tetrameric structure of the A2AR-D2R heteromer: first, ligand-independent allosteric modulations by the D2R that result in changes of the binding properties of A2AR ligands; second, differential modulation of the intrinsic efficacy of D2R ligands for G protein-dependent and independent signaling; third, the canonical antagonistic Gs-Gi interaction within the frame of the heteromer; and fourth, the ability of A2AR antagonists, including caffeine, to also exert the same allosteric modulations of D2R ligands than A2AR agonists, while A2AR agonists and antagonists counteract each other's effects. These findings can have important clinical implications when evaluating the use of A2AR antagonists. They also call for the need of monitoring caffeine intake when evaluating the effect of D2R ligands, when used as therapeutic agents in neuropsychiatric disorders or as probes in imaging studies. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.

Keywords: Adenosine A2A receptor; Caffeine; Dopamine D2 receptor; Heteromer; Parkinson's disease; Striatum.

Fig. 1

Scheme of different allosteric properties of ligands for the A_2AR-D₂ heterotetramer. A: Ability of A_2AR agonists (green circles; but also antagonists, see text) to decrease the affinity and intrinsic efficacy of D₂R agonists (orange circles; but also antagonists, see text). B: Ability of the D₂R to promote a negative cooperativity of a specific ligand, the A_2AR antagonist SCH 442416 (green squares). C: Ability of calneuron-1 (gray square with small red circles, representing Ca²⁺ ions) to promote functional selectivity of the allosteric modulations of A_2AR agonists (green circles) on D₂R agonists (orange circles) intrinsic efficacy (inhibiting D₂R-mediated MAPK activation but not G_i-mediated AC inhibition). D: Ability of caffeine or an A2AR antagonist (green square) to block the A2AR agonist (green circle)-mediated allosteric modulation of D₂R ligand (orange circles) functional properties.

Fig. 2

Brain maps showing significant differences in D₂R/D₃R availability (non-displaceable binding potential or BPND), between placebo and caffeine for the contrast Caffeine > Placebo. Threshold for significance corresponds to p<0.01, clusters > 100 voxels. Images are in radiological coordinatea where right corresponds to left. Modified from Volkow et al. (2015).