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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3748024?pdf=render |
| _version_ | 1828174926842953728 |
|---|---|
| author | Catherine E Erickson Rukhsana Gul Christopher P Blessing Jenny Nguyen Tammy Liu Lakshmi Pulakat Murat Bastepe Edwin K Jackson Bradley T Andresen |
| author_facet | Catherine E Erickson Rukhsana Gul Christopher P Blessing Jenny Nguyen Tammy Liu Lakshmi Pulakat Murat Bastepe Edwin K Jackson Bradley T Andresen |
| author_sort | Catherine E Erickson |
| collection | DOAJ |
| 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 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. |
| first_indexed | 2024-04-12T04:21:00Z |
| format | Article |
| id | doaj.art-47db710229054536b17959c760dc4743 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T04:21:00Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-47db710229054536b17959c760dc47432022-12-22T03:48:14ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0188e7198010.1371/journal.pone.0071980The β-blocker Nebivolol Is a GRK/β-arrestin biased agonist.Catherine E EricksonRukhsana GulChristopher P BlessingJenny NguyenTammy LiuLakshmi PulakatMurat BastepeEdwin K JacksonBradley T AndresenNebivolol, 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.http://europepmc.org/articles/PMC3748024?pdf=render |
| spellingShingle | Catherine E Erickson Rukhsana Gul Christopher P Blessing Jenny Nguyen Tammy Liu Lakshmi Pulakat Murat Bastepe Edwin K Jackson Bradley T Andresen The β-blocker Nebivolol Is a GRK/β-arrestin biased agonist. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC3748024?pdf=render |
| work_keys_str_mv | AT catherineeerickson thebblockernebivololisagrkbarrestinbiasedagonist AT rukhsanagul thebblockernebivololisagrkbarrestinbiasedagonist AT christopherpblessing thebblockernebivololisagrkbarrestinbiasedagonist AT jennynguyen thebblockernebivololisagrkbarrestinbiasedagonist AT tammyliu thebblockernebivololisagrkbarrestinbiasedagonist AT lakshmipulakat thebblockernebivololisagrkbarrestinbiasedagonist AT muratbastepe thebblockernebivololisagrkbarrestinbiasedagonist AT edwinkjackson thebblockernebivololisagrkbarrestinbiasedagonist AT bradleytandresen thebblockernebivololisagrkbarrestinbiasedagonist AT catherineeerickson bblockernebivololisagrkbarrestinbiasedagonist AT rukhsanagul bblockernebivololisagrkbarrestinbiasedagonist AT christopherpblessing bblockernebivololisagrkbarrestinbiasedagonist AT jennynguyen bblockernebivololisagrkbarrestinbiasedagonist AT tammyliu bblockernebivololisagrkbarrestinbiasedagonist AT lakshmipulakat bblockernebivololisagrkbarrestinbiasedagonist AT muratbastepe bblockernebivololisagrkbarrestinbiasedagonist AT edwinkjackson bblockernebivololisagrkbarrestinbiasedagonist AT bradleytandresen bblockernebivololisagrkbarrestinbiasedagonist |