Phosphoproteomic Analysis of Dopamine D2 Receptor Signaling Reveals Interplay of G Protein- and β-Arrestin-Mediated Effects

Wenk D, Khan S, Ignatchenko V, Hübner H, Gmeiner P, Weikert D, Pischetsrieder M, Kislinger T (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Journal of Proteome Research American Chemical Society

Book Volume: 22

Pages Range: 259-271

Journal Issue: 1

DOI: 10.1021/acs.jproteome.2c00707

Abstract

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).

Authors with CRIS profile

Harald Hübner Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie Dorothée Weikert Lehrstuhl für Pharmazeutische Chemie Monika Pischetsrieder Lehrstuhl für Lebensmittelchemie (Henriette-Schmidt-Burkhardt Lehrstuhl)

Involved external institutions

University of Toronto CA Canada (CA)

How to cite

APA:

Wenk, D., Khan, S., Ignatchenko, V., Hübner, H., Gmeiner, P., Weikert, D.,... Kislinger, T. (2023). Phosphoproteomic Analysis of Dopamine D2 Receptor Signaling Reveals Interplay of G Protein- and β-Arrestin-Mediated Effects. Journal of Proteome Research, 22(1), 259-271. https://doi.org/10.1021/acs.jproteome.2c00707

MLA:

Wenk, Deborah, et al. "Phosphoproteomic Analysis of Dopamine D2 Receptor Signaling Reveals Interplay of G Protein- and β-Arrestin-Mediated Effects." Journal of Proteome Research 22.1 (2023): 259-271.

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