Allosteric Interactions between Adenosine A2A and Dopamine D2 Receptors in Heteromeric Complexes: Biochemical and Pharmacological Characteristics, and Opportunities for PET Imaging

Abstract

Adenosine and dopamine interact antagonistically in living mammals. These interactions are mediated via adenosine A2A and dopamine D2 receptors (R). Stimulation of A2AR inhibits and blockade of A2AR enhances D2R-mediated locomotor activation and goal-directed behavior in rodents. In striatal membrane preparations, adenosine decreases both the affinity and the signal transduction of D2R via its interaction with A2AR. Reciprocal A2AR/D2R interactions occur mainly in striatopallidal GABAergic medium spiny neurons (MSNs) of the indirect pathway that are involved in motor control, and in striatal astrocytes. In the nucleus accumbens, they also take place in MSNs involved in reward-related behavior. A2AR and D2R co-aggregate, co-internalize, and co-desensitize. They are at very close distance in biomembranes and form heteromers. Antagonistic interactions between adenosine and dopamine are (at least partially) caused by allosteric receptor–receptor interactions within A2AR/D2R heteromeric complexes. Such interactions may be exploited in novel strategies for the treatment of Parkinson’s disease, schizophrenia, substance abuse, and perhaps also attention deficit-hyperactivity disorder. Little is known about shifting A2AR/D2R heteromer/homodimer equilibria in the brain. Positron emission tomography with suitable ligands may provide in vivo information about receptor crosstalk in the living organism. Some experimental approaches, and strategies for the design of novel imaging agents (e.g., heterobivalent ligands) are proposed in this review.

Dopamine D2 and Adenosine A2A Receptors Interaction on Ca2+ Current Modulation in a Rodent Model of Parkinsonism

“…Thereafter, in the continuous presence of the D 2 R agonist, pramipexole, a second application of CGS now increased and restored iCa 2+ to nearly previous values: 311 ± 58 pA (increase of 26.7 ± 5.9%), showing that A 2A R are present and can be activated in iSPNs if enabled by the previous activation of D 2 R, suggesting that the interaction between these receptors is necessary for A 2A R activity, and also, a negative cooperativity or functional antagonism between both receptors on iCa 2+ . This result parallels behavioral and biochemical antagonism previously reported ( Ferré et al, 1991 , 2008 ; Prasad et al, 2021 ; Preti et al, 2015 ; Stromberg et al, 2000 ; Yang et al, 1995 ). Figure 2A middle, shows representative I-V plots built from different moments during the time course denoted by numbers.…”

“…One hypothesis stands that A 2A R agonists or antagonists decreases intrinsic efficacy of any D 2 R ligand in a orthosteric fashion because the integrity of the D 2 -A 2A receptors oligomer is affected ( Azdad et al, 2009 ; Bonaventura et al, 2015 ). Although, it is not the objective of this work to elucidate the existence of heteromers, our results support this hypothesis ( Prasad et al, 2021 ) that is still debated ( Fredholm et al, 2011 ).…”

“…Notably however, when comparing non dopamine-depleted (control) with dopamine-depleted neurons from parkinsonian animals, pramipexole modulation appeared to be reduced in dopamine-depleted neurons when istradefylline was present ( Bonaventura et al, 2015 ; Casadó-Anguera et al, 2016 ). Modulation was reduced from 25.7 ± 3.0% in control neurons versus 14.9 ± 2.2 in dopamine-depleted neurons, showing that D 2 -A 2A receptors interaction goes both ways: the occupation of A 2A R by an antagonist ligand reduced the modulatory action of a D 2 R agonist during parkinsonism ( Bonaventura et al, 2015 ; Casadó-Anguera, 2016 ; Prasad et al, 2021 ), these electrophysiological results support parallel biochemical actions that have been attributed to D 2 -A 2A receptors oligomers and protein-protein interaction, that is, the non neutral action of A 2A receptor antagonists. By comparing percentages of iCa 2+ modulation by pramipexole in control and dopamine-depleted neurons in the presence and absence of istradefylline ( Figure 6 ) we found a decreased modulation by pramipexole in dopamine-depleted neurons when istradefylline was present (n-pramipexole = 11 neurons from different neurons from 10 different animals, n-pramipexole plus istradefylline = 10 neurons from different neurons from 9 different animals; Mann-Whitney U test, F = 7.0, * P = .0127).…”

“…Istradefylline failed to further reduce iSPNs activity while comparing samples of iSPNs previously treated with pramipexole, in fact, the number of active cells slightly increased, as though implying a reduction in pramipexole effects, however, parkinsonian activity did not return ( Prasad et al, 2021 ). These results support the hypothesis that istradefylline may be a good coadjuvant to L-DOPA therapy since it would not allow the increase in excitability caused by iCa 2+ restoration induced by A 2A R activation at the population level.…”

High spatio‐temporal resolution measurement of A1R and A2AR interactions combined with Iem‐spFRET and E‐FRET methods

“…G‐protein‐coupled receptors (GPCRs) belong to a large and diverse family of integral membrane protein, and have the propensity to form homo‐ and heterodimers [1]. Dysfunction of these dimers has been associated with multiple diseases, for example, schizophrenia (dopamine D 2 receptor (D 2 R) heterocomplexes [2, 3]), Parkinson's disease (adenosine A 2A receptor (A 2A R) and dopamine D 2 receptor (D 2 R) heterocomplexes [4–6]), preeclampsia (angiotensin II type 1 and bradykinin receptor B 2 heterodimer complexes [7]), depression (serotonin 1A receptor (5‐HT1A) and FGFR1 heterocomplexes [8, 9]). The interest in GPCR–GPCR interactions is ever‐expanding, as evidenced by the remarkable rise in publications in this field of research, with over 300 reports (data incomplete for 2019) covering GPCR multimers during the last 5 years [10].…”