Differential allosteric modulation within dopamine D(2)R - neurotensin NTS1R and D(2)R - serotonin 5-HT(2A)R receptor complexes gives bias to intracellular calcium signalling

Proceeding investigations of G protein-coupled receptor (GPCR) heterocomplexes have demonstrated that the dopamine D2 receptor (D(2)R), one of the hub receptors in the physiology of schizophrenia, interacts with both the neurotensin NTS1 (NTS1R) and the serotonin 5-HT(2A) receptor (5-HT(2A)R) in cell lines and rodent brain tissue. In situ proximity ligation assay and BRET-based saturation experiments confirmed interacting receptor assemblies in HEK293T and neuronal HT22 cells. The NTS1R agonist NT(8-13) reduces the Gα(q)-mediated calcium signal in the NTS1R-D(2)R complex compared to the NTS1R monomer which could be reversed by D(2)R antagonists. The bivalent ligand CS148 (NTS1R-agonistic, D(2)R-antagonistic) increased the calcium response addressing the dimer, consistent with the effect of the monovalent ligands suggesting an allosteric D(2)R-mediated modulation. In contrast, the 5-HT(2A)R-D(2)R heteromer did not show a calcium-altering receptor-receptor interaction. Despite their common coupling-preference for Gα(q), 5-HT(2A)R and NTS1R supposedly interact with D(2)R each in a unique mode. This remarkably diverse ligand-mediated signalling in two different D(2)R heteroreceptor complexes illustrates the complexity of receptor-receptor interactions and their potential of modifying cell responses to external stimuli. Therefore, GPCR heteromers may provide a very promising novel target for the therapy of neuropsychiatric disorders.