Functionally selective activation of the dopamine receptor D2 is mirrored by the protein expression profiles
Abstract The development of functionally selective or biased ligands is a promising approach towards drugs with less side effects. Biased ligands for G protein-coupled receptors can selectively induce G protein activation or β-arrestin recruitment. The consequences of this selective action on cellul...
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2021-02-01
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Online Access: | https://doi.org/10.1038/s41598-021-83038-x |
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doaj-e7271728fe8049c8a10edf9dadf9f5a62021-02-14T12:36:03ZengNature Publishing GroupScientific Reports2045-23222021-02-0111111410.1038/s41598-021-83038-xFunctionally selective activation of the dopamine receptor D2 is mirrored by the protein expression profilesDeborah Wenk0Vladimir Ignatchenko1Andrew Macklin2Harald Hübner3Peter Gmeiner4Dorothée Weikert5Monika Pischetsrieder6Thomas Kislinger7Food Chemistry, Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)Princess Margaret Cancer Centre, University Health NetworkPrincess Margaret Cancer Centre, University Health NetworkMedicinal Chemistry, Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)Medicinal Chemistry, Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)Medicinal Chemistry, Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)Food Chemistry, Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)Princess Margaret Cancer Centre, University Health NetworkAbstract The development of functionally selective or biased ligands is a promising approach towards drugs with less side effects. Biased ligands for G protein-coupled receptors can selectively induce G protein activation or β-arrestin recruitment. The consequences of this selective action on cellular functions, however, are not fully understood. Here, we investigated the impact of five biased and balanced dopamine D2 receptor agonists and antagonists on the global protein expression in HEK293T cells by untargeted nanoscale liquid chromatography–tandem mass spectrometry. The proteome analysis detected 5290 protein groups. Hierarchical clustering and principal component analysis based on the expression levels of 1462 differential proteins led to a separation of antagonists and balanced agonist from the control treatment, while the biased ligands demonstrated larger similarities to the control. Functional analysis of affected proteins revealed that the antagonists haloperidol and sulpiride regulated exocytosis and peroxisome function. The balanced agonist quinpirole, but not the functionally selective agonists induced a downregulation of proteins involved in synaptic signaling. The β-arrestin-preferring agonist BM138, however, regulated several proteins related to neuron function and the dopamine receptor-mediated signaling pathway itself. The G protein-selective partial agonist MS308 influenced rather broad functional terms such as DNA processing and mitochondrial translation.https://doi.org/10.1038/s41598-021-83038-x |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Deborah Wenk Vladimir Ignatchenko Andrew Macklin Harald Hübner Peter Gmeiner Dorothée Weikert Monika Pischetsrieder Thomas Kislinger |
spellingShingle |
Deborah Wenk Vladimir Ignatchenko Andrew Macklin Harald Hübner Peter Gmeiner Dorothée Weikert Monika Pischetsrieder Thomas Kislinger Functionally selective activation of the dopamine receptor D2 is mirrored by the protein expression profiles Scientific Reports |
author_facet |
Deborah Wenk Vladimir Ignatchenko Andrew Macklin Harald Hübner Peter Gmeiner Dorothée Weikert Monika Pischetsrieder Thomas Kislinger |
author_sort |
Deborah Wenk |
title |
Functionally selective activation of the dopamine receptor D2 is mirrored by the protein expression profiles |
title_short |
Functionally selective activation of the dopamine receptor D2 is mirrored by the protein expression profiles |
title_full |
Functionally selective activation of the dopamine receptor D2 is mirrored by the protein expression profiles |
title_fullStr |
Functionally selective activation of the dopamine receptor D2 is mirrored by the protein expression profiles |
title_full_unstemmed |
Functionally selective activation of the dopamine receptor D2 is mirrored by the protein expression profiles |
title_sort |
functionally selective activation of the dopamine receptor d2 is mirrored by the protein expression profiles |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-02-01 |
description |
Abstract The development of functionally selective or biased ligands is a promising approach towards drugs with less side effects. Biased ligands for G protein-coupled receptors can selectively induce G protein activation or β-arrestin recruitment. The consequences of this selective action on cellular functions, however, are not fully understood. Here, we investigated the impact of five biased and balanced dopamine D2 receptor agonists and antagonists on the global protein expression in HEK293T cells by untargeted nanoscale liquid chromatography–tandem mass spectrometry. The proteome analysis detected 5290 protein groups. Hierarchical clustering and principal component analysis based on the expression levels of 1462 differential proteins led to a separation of antagonists and balanced agonist from the control treatment, while the biased ligands demonstrated larger similarities to the control. Functional analysis of affected proteins revealed that the antagonists haloperidol and sulpiride regulated exocytosis and peroxisome function. The balanced agonist quinpirole, but not the functionally selective agonists induced a downregulation of proteins involved in synaptic signaling. The β-arrestin-preferring agonist BM138, however, regulated several proteins related to neuron function and the dopamine receptor-mediated signaling pathway itself. The G protein-selective partial agonist MS308 influenced rather broad functional terms such as DNA processing and mitochondrial translation. |
url |
https://doi.org/10.1038/s41598-021-83038-x |
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