posted on 2022-12-12, 19:40authored byDeborah Wenk, Shahbaz Khan, Vladimir Ignatchenko, Harald Hübner, Peter Gmeiner, Dorothee Weikert, Monika Pischetsrieder, Thomas Kislinger
Leveraging biased signaling of G protein-coupled receptors
has
been proposed as a promising strategy for the development of drugs
with higher specificity. However, the consequences of selectively
targeting G protein- or β-arrestin-mediated signaling on cellular
functions are not comprehensively understood. In this study, we utilized
phosphoproteomics to gain a systematic overview of signaling induced
by the four biased and balanced dopamine D2 receptor (D2R) ligands MS308, BM138, quinpirole, and sulpiride in an in vitro
D2R transfection model. Quantification of 14,160 phosphosites
revealed a low impact of the partial G protein agonist MS308 on cellular
protein phosphorylation, as well as surprising similarities between
the balanced agonist quinpirole and the inverse agonist sulpiride.
Analysis of the temporal profiles of ligand-induced phosphorylation
events showed a transient impact of the G protein-selective agonist
MS308, whereas the β-arrestin-preferring agonist BM138 elicited
a delayed, but more pronounced response. Functional enrichment analysis
of ligand-impacted phosphoproteins and treatment-linked kinases confirmed
multiple known functions of D2R signaling while also revealing
novel effects, for example of MS308 on sterol regulatory element-binding
protein-related gene expression. All raw data were deposited in MassIVE
(MSV000089457).