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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Autores principales:	Deborah Wenk, Vladimir Ignatchenko, Andrew Macklin, Harald Hübner, Peter Gmeiner, Dorothée Weikert, Monika Pischetsrieder, Thomas Kislinger
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e7271728fe8049c8a10edf9dadf9f5a6
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spelling	oai:doaj.org-article:e7271728fe8049c8a10edf9dadf9f5a62021-12-02T14:11:32ZFunctionally selective activation of the dopamine receptor D2 is mirrored by the protein expression profiles10.1038/s41598-021-83038-x2045-2322https://doaj.org/article/e7271728fe8049c8a10edf9dadf9f5a62021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83038-xhttps://doaj.org/toc/2045-2322Abstract 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.Deborah WenkVladimir IgnatchenkoAndrew MacklinHarald HübnerPeter GmeinerDorothée WeikertMonika PischetsriederThomas KislingerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
author	Deborah Wenk Vladimir Ignatchenko Andrew Macklin Harald Hübner Peter Gmeiner Dorothée Weikert Monika Pischetsrieder Thomas Kislinger
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 Portfolio
publishDate	2021
url	https://doaj.org/article/e7271728fe8049c8a10edf9dadf9f5a6
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Functionally selective activation of the dopamine receptor D2 is mirrored by the protein expression profiles

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