Bivalent ligands promote endosomal trafficking of the dopamine D3 receptor-neurotensin receptor 1 heterodimer
Julian Budzinski, Simone Maschauer, Hiroyuki Kobayashi, Pierre Couvineau, Hannah Vogt, Peter Gmeiner, Anna Roggenhofer, Olaf Prante, Michel Bouvier, Dorothée Weikert
Abstract
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 (D 3 R) 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 D 3 R-NTSR1 dimers results in picomolar binding affinity and high selectivity compared to the binding to monomeric receptors. Specificity of the ligands for the D 3 R-NTSR1 receptor pair over D 2 R-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 D 3 R into endosomes via recruitment of β-arrestin, highlighting a potential mechanism for dimer-specific receptor trafficking and signalling.