Heterodimerization of dopamine receptors: new insights into functional and therapeutic significance

G-protein-coupled receptors (GPCRs) exist both as monomers and also as dimers or higher-order oligomers, representing assemblies either with their peers or with other classes of GPCR (heterodimers). The pharmacological profiles of heterodimers often differ from the corresponding monomers or homodimers. Heterodimerization of dopamine receptors has been shown for both the D-1/D-5 and D-2/D-3/D-4 receptor families, which couple positively and negatively, respectively, to adenylyl cyclase. Notably, heterodimers are formed by: D-1 and adenosine A(1) receptors; D-2 or D-3 and adenosine A(2) receptors; and D-2 and somatostatin SST5 receptors. Further, D-1, D-2 and D-3 receptors physically assemble into functional D-1/D-2, D-1/D-3 and D-2/D-3 heterodimers possessing binding and coupling profiles distinct from the respective monomers. This article reviews data on dopamine D-3/D-2 and D-3/D-1 heterodimers, including observations that some antiparkinsonian agents - such as the preferential high-efficacy D3 versus D2 receptor agonists, pramipexole and ropinirole - show amplified potency at D-3/D-2 heterodimers versus constituent monomers, and others in contrast, such as the D-3/D-2 receptor agonist pergolide, show no difference. This article also discusses allosteric modulation amongst heterodimeric dopamine receptors, whereby agonist actions at one member of a heterodimer influence functional coupling at the other protomer. Finally, it presents data showing that, in cells co-transfected with D-3 and D-1 receptors, long-termexposure to pramipexole and ropinirole (which possess negligible affinities for D-1 sites) elicits supersensitivity of D-1 receptor-activated adenylyl cyclase, and conversely, D-3/D-2 receptor agonists such as apomorphine and bromocriptine (which also act as D-1 receptor agonists) do not. A hypothetical relationship between these observations and the exacerbation of gambling in Parkinson's disease by antiparkinsonian agents is discussed. (C) 2009 Elsevier Ltd. All rights reserved.