Cross-Receptor Interactions between Dopamine D2Land Neurotensin NTS1Receptors Modulate Binding Affinities of Dopaminergics

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Abstract
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 D2L 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 D2 was observed in presence of neurotensin. To correlate between the functional properties of dopaminergic agents and the magnitude of neurotensin-induced modulation of D2L binding affinities in cells coexpressing D2L 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 D2 agonist FAUC 326 displayed a 34-fold decrease of binding affinity in cells coexpressing D2L and NTS1.

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