The receptor–receptor interaction field began with the studies on the neuropeptide–monoamine receptor–receptor interactions in membrane preparations in the early 1980s, which altered especially the affinity of the monoamine receptor subtypes. It was proposed that their interactions in the plasma membrane took place in postulated heteroreceptor complexes of GPCRs which could involve the participation of adapter proteins (Fuxe et al, 2014). Now the receptor field in the CNS has expanded and includes not only the monomers but also homo and heteroreceptor complexes with receptor assemblies of unknown stoichiometry and geometry together with adapter proteins (Figure 1) as novel targets for treatment of neurological and mental diseases. In the beginning bivalent compounds were developed like norbinaltorphimine to obtain selective opioid receptor antagonists (Portoghese, 1992).

Figure 1
figure 1

Illustration of the antagonistic allosteric receptor–receptor interactions in the A2AR-D2R heteroreceptor complexes with several possible receptor stoichiometries from heterodimers to higher order heteromers of various types (heterotrimer and heterotetramer are shown; lower part) with the participation of adapter proteins (Ater). These proteins may participate in the mediation of the allosteric interaction by eg, guiding the receptors towards each other through a scaffolding function. Such actions may also regulate the time of the heteromerization from being transient to becoming more stable and long lasting. The major allosteric interaction appears to be an antagonistic A2AR-D2R interaction by which the agonist-activated A2AR protomer inhibits the D2R protomer recognition (reduced affinity) and Gi/o mediated signaling. D2R protomer becomes switched towards a state dominated by beta-arrestin-mediated signaling (far right). The heterocomplexes are in balance especially with the corresponding A2AR and D2R homoreceptor complexes (upper part) but also with other collocated D2R heterocomplexes and A2AR heterocomplexes (not shown) in the synapses and their extrasynaptic regions in the striato-pallidal GABA neurons. Although not shown, the adapter proteins also participate in modulating the organization and function of the A2AR and D2R homodimers and their higher order homoreceptor complexes.

PowerPoint slide

It is of high interest that dopamine D2R receptors form higher order homoreceptor complexes at physiological expression levels in living cells as was demonstrated using protein complementation assays combined with resonance energy transfer (Guo et al, 2008). Also, it was demonstrated that allosteric mechanisms are in operation between protomers of D2R homodimers that modulate their activation (Han et al, 2009). Using a functional complementation assay it became possible to evaluate the D2R homodimeric functional unit and directly study their receptor-G protein interactions. The evidence suggests an asymmetrical activated D2R homodimer where the second D2R protomer inhibits signaling.

The allosteric receptor–receptor interactions in heteroreceptor complexes give diversity, specificity and bias to the receptor protomers due to conformational changes in discrete domains leading to changes in receptor protomer function and their pharmacology (Fuxe et al, 2014; George et al, 2014). The discovery of the adenosine A2AR-D2R heteroreceptor complexes in the dorsal striato-pallidal GABA neurons with antagonistic A2AR-D2R receptor–receptor interactions reducing D2R signaling (Figure 1) led to the development of A2AR antagonists for treatment of Parkinson’s disease (Fuxe et al, 2014). The motor complications found with levodopa such as dyskinesias and wearing off phenomena can involve a reorganization of these heteroreceptor complexes involving also a disbalance with A2AR and D2R homoreceptor complexes. Increased knowledge of the changes in the heteroreceptor complexes and their function in neurological and mental diseases may lead to the discovery of novel therapeutics.

Neurotrophic and antidepressant effects of 5-HT in brain may, in part, be mediated by activation of the 5-HT1A receptor protomer in the hippocampal and midbrain raphe fibroblast growth factor receptor 1 (FGFR1)-5-HT1A heterocomplexes enhancing the FGFR1 signaling (Borroto-Escuela et al, 2015). The FGFR1-5-HT1A heteroreceptor complex likely represents a novel target for antidepressant drugs and offers a new strategy for treatment of depression.

Taken together, GPCR heteroreceptor complexes and their receptor–receptor interactions represent a new fundamental principle in molecular medicine for integration of transmitter signals in the plasma membrane. A novel understanding of the molecular basis of CNS diseases is given together with new strategies for their treatment by targeting heteroreceptor complexes based on a new pharmacology with combined treatment, multi-targeted drugs and heterobivalent drugs. Our perspective on the future of research on heteroreceptor complexes is the further development and employment of multiple techniques for use in cellular models, brain tissue and in vivo studies to understand their role in discrete brain circuits. The advancement of the proximity ligation assay will be of special importance as will be the development of selective heterobivalent compounds for the heterocomplexes.

Funding and disclosure

The authors declare no conflict of interest.