期刊
ACS CHEMICAL NEUROSCIENCE
卷 2, 期 6, 页码 308-316出版社
AMER CHEMICAL SOC
DOI: 10.1021/cn200020y
关键词
Dopamine D-2L receptor; neurotensin receptor 1; NTS1; G-protein coupled receptor; GPCR; coexpression; intramembrane receptor-receptor interaction; negative cooperativity; binding affinity; coimmunoprecipitation; dimer; heteromer
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.
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