Bivalent ligands promote endosomal trafficking of the dopamine D3 receptor-neurotensin receptor 1 heterodimer
Budzinski J, Maschauer S, Kobayashi H, Couvineau P, Vogt H, Gmeiner P, Roggenhofer A, Prante O, Bouvier M, Weikert D (2021)
Publication Type: Journal article
Publication year: 2021
Journal
Book Volume: 4
Article Number: 1062
Journal Issue: 1
DOI: 10.1038/s42003-021-02574-4
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.
Authors with CRIS profile
Julian Budzinski
Lehrstuhl für Pharmazeutische Chemie
Simone Maschauer
Department of Nuclear Medicine
Hannah Vogt
Lehrstuhl für Pharmazeutische Chemie
Peter Gmeiner
Lehrstuhl für Pharmazeutische Chemie
Anna Pirzer
Professur für Pharmazeutische Chemie
Olaf Prante
Professur für Molekulare Bildgebung und Radiochemie
Dorothée Weikert
Lehrstuhl für Pharmazeutische Chemie
Involved external institutions
Canada (CA)How to cite
APA:
Budzinski, J., Maschauer, S., Kobayashi, H., Couvineau, P., Vogt, H., Gmeiner, P.,... Weikert, D. (2021). Bivalent ligands promote endosomal trafficking of the dopamine D3 receptor-neurotensin receptor 1 heterodimer. Communications Biology, 4(1). https://doi.org/10.1038/s42003-021-02574-4
MLA:
Budzinski, Julian, et al. "Bivalent ligands promote endosomal trafficking of the dopamine D3 receptor-neurotensin receptor 1 heterodimer." Communications Biology 4.1 (2021).
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