Show simple item record

dc.contributor.authorErickson, Catherine E.en_US
dc.contributor.authorGul, Rukhsanaen_US
dc.contributor.authorBlessing, Christopher P.en_US
dc.contributor.authorNguyen, Jennyen_US
dc.contributor.authorLiu, Tammyen_US
dc.contributor.authorPulakat, Lakshmien_US
dc.contributor.authorBastepe, Muraten_US
dc.contributor.authorJackson, Edwin K.en_US
dc.contributor.authorAndresen, Bradley T.en_US
dc.date.accessioned2014-03-01T02:25:04Z
dc.date.issued2013en_US
dc.identifier.citationErickson, Catherine E., Rukhsana Gul, Christopher P. Blessing, Jenny Nguyen, Tammy Liu, Lakshmi Pulakat, Murat Bastepe, Edwin K. Jackson, and Bradley T. Andresen. 2013. “The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist.” PLoS ONE 8 (8): e71980. doi:10.1371/journal.pone.0071980. http://dx.doi.org/10.1371/journal.pone.0071980.en
dc.identifier.issn1932-6203en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11855853
dc.description.abstractNebivolol, 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 Gαs 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 β2-ARs, and HL-1 cardiac myocytes that express β1- and β2-ARs and no detectable β3-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 β2-AR, and likely β1-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 β1- and/or β2-ARs.en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.relation.isversionofdoi:10.1371/journal.pone.0071980en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748024/pdf/en
dash.licenseLAAen_US
dc.subjectBiologyen
dc.subjectMolecular Cell Biologyen
dc.subjectSignal Transductionen
dc.subjectMembrane Receptor Signalingen
dc.subjectNeurotransmitter Receptor Signalingen
dc.subjectSignaling in Cellular Processesen
dc.subjectG-Protein Signalingen
dc.subjectSignaling Pathwaysen
dc.subjectAdrenergic Signal Transductionen
dc.subjectMathematicsen
dc.subjectStatisticsen
dc.subjectBiostatisticsen
dc.subjectMedicineen
dc.subjectCardiovascularen
dc.subjectDrugs and Devicesen
dc.subjectCardiovascular Pharmacologyen
dc.titleThe β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonisten
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalPLoS ONEen
dash.depositing.authorBastepe, Muraten_US
dc.date.available2014-03-01T02:25:04Z
dc.identifier.doi10.1371/journal.pone.0071980*
dash.contributor.affiliatedBastepe, Murat


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record