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 D<inf>1</inf>/D<inf>5</inf> and D<inf>2</inf>/D<inf>3</inf>/D<inf>4</inf> receptor families form homo- and heteromers. The present article focuses on D<inf>3</inf> receptor homo- and heteromers, in particular, those formed in association with their D<inf>2</inf> counterparts. We highlight the binding profiles and mechanisms of interaction with D<inf>3</inf>-D<inf>3</inf> homomers and D<inf>3</inf>-D<inf>2</inf> heteromers of: first, the PET ligand and potent agonist [<sup>11</sup>C]-(+)-PHNO; second, the novel, bitopic/allosteric dopamine D<inf>3</inf> receptor antagonist, SB269,652; and third, diverse partial agonists like antipsychotic and aripiprazole. Molecular mechanisms of interplay between the two protomers of heteromeric D<inf>3</inf>-D<inf>2</inf> 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, D<inf>1</inf> 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 D<inf>3</inf> as well as D<inf>2</inf> and D<inf>1</inf> 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.
|Titolo:||Novel dimensions of D<inf>3</inf> receptor function: Focus on heterodimerisation, transactivation and allosteric modulation|
MAGGIO, Roberto (Corresponding)
|Data di pubblicazione:||2015|
|Appare nelle tipologie:||1.1 Articolo in rivista|