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The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist
Nebivolol, a third generation β-adrenoceptor (β-AR) antagonist (β-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748024/ https://www.ncbi.nlm.nih.gov/pubmed/23977191 http://dx.doi.org/10.1371/journal.pone.0071980 |
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author | Erickson, Catherine E. Gul, Rukhsana Blessing, Christopher P. Nguyen, Jenny Liu, Tammy Pulakat, Lakshmi Bastepe, Murat Jackson, Edwin K. Andresen, Bradley T. |
author_facet | Erickson, Catherine E. Gul, Rukhsana Blessing, Christopher P. Nguyen, Jenny Liu, Tammy Pulakat, Lakshmi Bastepe, Murat Jackson, Edwin K. Andresen, Bradley T. |
author_sort | Erickson, Catherine E. |
collection | PubMed |
description | Nebivolol, a third generation β-adrenoceptor (β-AR) antagonist (β-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action of nebivolol. Carvedilol is another β-blocker that induces NO production. A prominent pharmacological mechanism of carvedilol is biased agonism that is independent of Gα(s) and involves G protein-coupled receptor kinase (GRK)/β-arrestin signaling with downstream activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). Due to the pharmacological similarities between nebivolol and carvedilol, we hypothesized that nebivolol is also a GRK/β-arrestin biased agonist. We tested this hypothesis utilizing mouse embryonic fibroblasts (MEFs) that solely express β(2)-ARs, and HL-1 cardiac myocytes that express β(1)- and β(2)-ARs and no detectable β(3)-ARs. We confirmed previous reports that nebivolol does not significantly alter cAMP levels and thus is not a classical agonist. Moreover, in both cell types, nebivolol induced rapid internalization of β-ARs indicating that nebivolol is also not a classical β-blocker. Furthermore, nebivolol treatment resulted in a time-dependent phosphorylation of ERK that was indistinguishable from carvedilol and similar in duration, but not amplitude, to isoproterenol. Nebivolol-mediated phosphorylation of ERK was sensitive to propranolol (non-selective β-AR-blocker), AG1478 (EGFR inhibitor), indicating that the signaling emanates from β-ARs and involves the EGFR. Furthermore, in MEFs, nebivolol-mediated phosphorylation of ERK was sensitive to pharmacological inhibition of GRK2 as well as siRNA knockdown of β-arrestin 1/2. Additionally, nebivolol induced redistribution of β-arrestin 2 from a diffuse staining pattern into more intense punctate spots. We conclude that nebivolol is a β(2)-AR, and likely β(1)-AR, GRK/β-arrestin biased agonist, which suggests that some of the unique clinically beneficial effects of nebivolol may be due to biased agonism at β(1)- and/or β(2)-ARs. |
format | Online Article Text |
id | pubmed-3748024 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37480242013-08-23 The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist Erickson, Catherine E. Gul, Rukhsana Blessing, Christopher P. Nguyen, Jenny Liu, Tammy Pulakat, Lakshmi Bastepe, Murat Jackson, Edwin K. Andresen, Bradley T. PLoS One Research Article Nebivolol, a third generation β-adrenoceptor (β-AR) antagonist (β-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action of nebivolol. Carvedilol is another β-blocker that induces NO production. A prominent pharmacological mechanism of carvedilol is biased agonism that is independent of Gα(s) and involves G protein-coupled receptor kinase (GRK)/β-arrestin signaling with downstream activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). Due to the pharmacological similarities between nebivolol and carvedilol, we hypothesized that nebivolol is also a GRK/β-arrestin biased agonist. We tested this hypothesis utilizing mouse embryonic fibroblasts (MEFs) that solely express β(2)-ARs, and HL-1 cardiac myocytes that express β(1)- and β(2)-ARs and no detectable β(3)-ARs. We confirmed previous reports that nebivolol does not significantly alter cAMP levels and thus is not a classical agonist. Moreover, in both cell types, nebivolol induced rapid internalization of β-ARs indicating that nebivolol is also not a classical β-blocker. Furthermore, nebivolol treatment resulted in a time-dependent phosphorylation of ERK that was indistinguishable from carvedilol and similar in duration, but not amplitude, to isoproterenol. Nebivolol-mediated phosphorylation of ERK was sensitive to propranolol (non-selective β-AR-blocker), AG1478 (EGFR inhibitor), indicating that the signaling emanates from β-ARs and involves the EGFR. Furthermore, in MEFs, nebivolol-mediated phosphorylation of ERK was sensitive to pharmacological inhibition of GRK2 as well as siRNA knockdown of β-arrestin 1/2. Additionally, nebivolol induced redistribution of β-arrestin 2 from a diffuse staining pattern into more intense punctate spots. We conclude that nebivolol is a β(2)-AR, and likely β(1)-AR, GRK/β-arrestin biased agonist, which suggests that some of the unique clinically beneficial effects of nebivolol may be due to biased agonism at β(1)- and/or β(2)-ARs. Public Library of Science 2013-08-20 /pmc/articles/PMC3748024/ /pubmed/23977191 http://dx.doi.org/10.1371/journal.pone.0071980 Text en © 2013 Erickson et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Erickson, Catherine E. Gul, Rukhsana Blessing, Christopher P. Nguyen, Jenny Liu, Tammy Pulakat, Lakshmi Bastepe, Murat Jackson, Edwin K. Andresen, Bradley T. The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist |
title | The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist |
title_full | The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist |
title_fullStr | The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist |
title_full_unstemmed | The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist |
title_short | The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist |
title_sort | β-blocker nebivolol is a grk/β-arrestin biased agonist |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748024/ https://www.ncbi.nlm.nih.gov/pubmed/23977191 http://dx.doi.org/10.1371/journal.pone.0071980 |
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