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Bivalent ligands promote endosomal trafficking of the dopamine D3 receptor-neurotensin receptor 1 heterodimer.
- Source :
-
Communications Biology . 9/10/2021, Vol. 4 Issue 1, p1-13. 13p. - Publication Year :
- 2021
-
Abstract
- Bivalent ligands are composed of two pharmacophores connected by a spacer of variable size. These ligands are able to simultaneously recognize two binding sites, for example in a G protein-coupled receptor heterodimer, resulting in enhanced binding affinity. Taking advantage of previously described heterobivalent dopamine-neurotensin receptor ligands, we demonstrate specific interactions between dopamine D3 (D3R) and neurotensin receptor 1 (NTSR1), two receptors with expression in overlapping brain areas that are associated with neuropsychiatric diseases and addiction. Bivalent ligand binding to D3R-NTSR1 dimers results in picomolar binding affinity and high selectivity compared to the binding to monomeric receptors. Specificity of the ligands for the D3R-NTSR1 receptor pair over D2R-NTSR1 dimers can be achieved by a careful choice of the linker length. Bivalent ligands enhance and stabilize the receptor-receptor interaction leading to NTSR1-controlled internalization of D3R into endosomes via recruitment of β-arrestin, highlighting a potential mechanism for dimer-specific receptor trafficking and signalling. Budzinski et al use bivalent ligands, BRET assays and radioligand competition to demonstrate a specific interaction between two receptors associated with neuropsychiatric diseases and addiction, dopamine D3 (D3R) and neurotensin receptor 1. They show that the bivalent ligands promote endosomal trafficking of D3R, suggesting a potential role for dimerization in vivo. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 23993642
- Volume :
- 4
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Communications Biology
- Publication Type :
- Academic Journal
- Accession number :
- 152372738
- Full Text :
- https://doi.org/10.1038/s42003-021-02574-4