Novel dimensions of D3 receptor function: Focus on heterodimerisation, transactivation and allosteric modulation

The brain׳s complexity derives not only from the way the intricate network of neurons is wired, but also by protein complexes that recognize and decode chemical information. G protein-coupled receptors (GPCRs) represent the most abundant family of proteins mediating neurotransmission in the brain, and their ability to form homo- and heteromers which amplifies the scope for synaptic communication and fine-tuning. Dopamine receptors are important drug targets and members of both the D1/D5 and D2/D3/D4 receptor families form homo- and heteromers. The present article focuses on D3 receptor homo- and heteromers, in particular, those formed in association with their D2 counterparts. We highlight the binding profiles and mechanisms of interaction with D3–D3 homomers and D3–D2 heteromers of: first, the PET ligand and potent agonist [11C]-(+)-PHNO; second, the novel, bitopic/allosteric dopamine D3 receptor antagonist, SB269,652; and third, diverse partial agonists like antipsychotic and aripiprazole. Molecular mechanisms of interplay between the two protomers of heteromeric D3–D2 complexes are likewise discussed: for example, “transactivation”, whereby recruitment of one member of a heteromer harnesses signalling pathways is normally coupled to the other protomer. Finally, D1 receptor heteromers are also taken into consideration in deciphering the nature of interfaces required to stabilize dimeric assemblies and permit their interaction with G proteins. Improved understanding of D3 as well as D2 and D1 receptor complexes should yield important insights into their physiological roles and pathological significance, and permit the development of novel drug classes with potentially distinctive functional profiles and improved therapeutic windows.