The receptor-receptor interaction field began with the studies on the neuropeptide-monoamine receptor-receptor interactions in membrane preparations in the early 1980s. It was proposed that their interactions in the plasma membrane took place in postulated heteroreceptor complexes of GPCRs. 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 as novel targets for treatment of neurological and mental diseases. 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.
The discovery of the adenosine A2AR- D2R heteroreceptor complexes in the dorsal and ventral striato-pallidal GABA neurons with antagonistic A2AR-D2R receptor-receptor interactions reducing D2R signaling led to the development of A2AR antagonists and agonists for treatment of Parkinson’s disease and cocaine use disorder, respectively. The A2AR agonist can exert their anti-cocaine actions through antagonistic interactions with the D2R protomer in the heteroreceptor complexes located in the ventral striato-pallidal GABA neurons of the ventral striatum increasing activity in this anti-reward system. The motor complications found with levodopa such as dyskinesias and wearing off phenomena can involve a reorganization of these heteroreceptor complexes in the dorsal striatum 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 FGFR1–5-HT1A heterocomplexes enhancing FGFR1 signaling. The FGFR1-5-HT1A heteroreceptor complex likely represents a novel target for antidepressant drugs and offers a new strategy for treatment of depression.
This research gives a novel understanding of the molecular basis of CNS diseases as well as 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 and in brain disease and its treatment.
Illustration of the antagonistic allosteric receptor-receptor interactions in the A2AR-D2R heteroreceptor complexes with several possible receptor stoichiometries
Adapter proteins (Ater) may participate in the mediation of the allosteric interaction by e.g., 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 and Gi/o mediated signaling. D2R protomer becomes switched towards a state dominated by beta-arrestin mediated signaling. The heterocomplexes are in balance especially with the corresponding A2AR and D2R homoreceptor complexes but also with other colocated D2R heterocomplexes and A2AR heterocomplexes (not shown) in the synapses and their extrasynaptic regions in the striato-pallidal GABA neurons.
FGFR1-5-HT1A Heteroreceptor Complexes: Implications for Understanding and Treating Major Depression.
Trends Neurosci. 2016 Jan;39(1):5-15
Heteroreceptor Complexes and their Allosteric Receptor-Receptor Interactions as a Novel Biological Principle for Integration of Communication in the CNS: Targets for Drug Development.
Neuropsychopharmacology 2016 Jan;41(1):380-2
The role of transmitter diffusion and flow versus extracellular vesicles in volume transmission in the brain neural-glial networks.
Philos. Trans. R. Soc. Lond., B, Biol. Sci. 2015 Jul;370(1672):
The G protein-coupled receptor heterodimer network (GPCR-HetNet) and its hub components.
Int J Mol Sci 2014 May;15(5):8570-90
Moonlighting proteins and protein-protein interactions as neurotherapeutic targets in the G protein-coupled receptor field.
Neuropsychopharmacology 2014 Jan;39(1):131-55
Dasiel O. Borroto-Escuela - postdoc
David Savelli - PhD student
Xiang Li - PhD student
Elisa Barbieri - MSc student