科研之友
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摘要
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-1/D-5 and D-2/D-3/D-4 receptor families form homo- and heteromers. The present article focuses on D-3 receptor homo- and heteromers, in particular, those formed in association with their D-2 counterparts. We highlight the binding profiles and mechanisms of interaction with D-3-D-3 homomers and D-3-D-2 heteromers of: first, the PET ligand and potent agonist [C-11]-(+)-PHNO; second, the novel, bitopic/allosteric dopamine D-3 receptor antagonist, SB269,652; and third, diverse partial agonists like antipsychotic and aripiprazole. Molecular mechanisms of interplay between the two protomers of heteromeric D-3-D-2 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-1 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-3 as well as D-2 and D-1 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.
- 出版日期2015-9
