Evidence for the heterotetrameric structure of the adenosine A_2A–dopamine D₂ receptor complex

Heteromers of G-protein-coupled receptors (GPCRs) have emerged as potential novel targets for drug development. Accumulating evidence indicates that GPCRs can form homodimers and heteromers, with homodimers being the predominant species and oligomeric receptors being formed as multiples of dimers. Recently, heterotetrameric structures have been proposed for dopamine D₁ receptor (D₁R)–dopamine D₃ receptor (D₃R) and adenosine A_2A receptor (A_2AR)–dopamine D₂ receptor (D₂R) heteromers. The structural model proposed for these complexes is a heteromer constituted by two receptor homodimers. The existence of GPCR homodimers and heteromers provides a structural basis for inter-protomer allosteric mechanisms that might account for a multiplicity of unique pharmacological properties. In this review, we focus on the A_2AR–D₂R heterotetramer as an example of an oligomeric structure that is key in the modulation of striatal neuronal function. We also review the interfaces involved in this and other recently reported heteromers of GPCRs. Furthermore, we discuss several published studies showing the ex vivo expression of A_2AR–D₂R heteromers. The ability of A_2AR agonists to decrease the affinity of D₂R agonists has been reported and, on the basis of this interaction, A_2AR antagonists have been proposed as potential drugs for the treatment of Parkinson's disease. The heterotetrameric structure of the A_2AR–D₂R complex offers a novel model that can provide new clues about how to adjust the drug dosage to the expected levels of endogenous adenosine.