Allosteric mechanisms in the adenosine A2A-dopamine D2 receptor heteromer

Abstract

The pentameric structure constituted by one G protein coupled receptor (GPCR) homodimer and one heterotrimeric 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 their preferred G protein. GPCR homomers and heteromers can act as the conduit of allosteric interactions of orthosteric ligands. One ligand binding to one of the receptor units (protomer) modulates the properties of the same or another orthosteric ligand binding to another protomer. The agonist/agonist interaction in the adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromer, by which A2AR agonists decrease the affinity of D2R agonists, constitutes a well-known example and gave the first rationale for the use of A2AR antagonists in Parkinson's disease. We review most recent studies that extend those findings to, first, ligand-independent allosteric modulations of the D2R protomer that result in changes of the binding properties of A2AR ligands in the A2AR-D2R heteromer; second, the differential modulation of the intrinsic efficacy of D2R ligands for G protein-dependent and independent signaling; and third, the existence of the canonical antagonistic Gs-Gi interaction within the frame of the A2AR-D2R heteromer. These studies support the heterotetrameric structure of GPCR heteromers.