Cross-Receptor Interactions between Dopamine D2L and Neurotensin NTS1 Receptors Modulate Binding Affinities of Dopaminergics

Dopaminergic systems have been described to functionally interact with the neuromodulatory peptide neurotensin. Employing fluorescence detected coimmunoprecipitation and radioligand binding experiments, we herein demonstrate that coexpression of dopamine D-2L receptor and the neurotensin receptor subtype NTS1 leads to physical interaction and the formation of heteromers in transfected human embryonic kidney 293 cells. In this in vitro system, a trans-inhibitory effect on the agonist binding affinity of D-2 was observed in presence of neurotensin. To correlate between the functional properties of dopaminergic agents and the magnitude of neurotensin-induced modulation of D-2L binding affinities in cells coexpressing D-2L and NTS1, a structurally diverse set of dopamine receptor agonists, partial agonists, and antagonists was tested. Ligand specific profiles indicating substantial bias between ligand efficacy and transmodulation were discovered, suggesting a heteromerization-based functional selectivity. In the presence of neurotensin, the novel D-2 agonist FAUC 326 displayed a 34-fold decrease of binding affinity in cells coexpressing D-2L and NTS1.