文章基本信息

标题：Differential allosteric modulation within dopamine D2R - neurotensin NTS1R and D2R - serotonin 5-HT2AR receptor complexes gives bias to intracellular calcium signalling
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作者：Michael Plach ; Thorsten Schäfer ; Dasiel Oscar Borroto-Escuela 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2019
卷号：9
期号：1
页码：1-11
DOI：10.1038/s41598-019-52540-8
出版社：Springer Nature
摘要：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.