β-Blockers alprenolol and carvedilol stimulate β-arrestin-mediated EGFR transactivation

Kim, Il-man; Tilley, Douglas G.; Chen, Juhsien; Salazar, Natasha C.; Whalen, Erin J.; Violin, Jonathan D.; Rockman, Howard A.

doi:10.1073/pnas.0804745105

Cited by 239 publications

(270 citation statements)

References 44 publications

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“…For example, carvedilol has been shown to promote βAR-mediated EGFR transactivation in a β-arrestin-dependent manner (20). In HEK293 cells stably overexpressing FLAG-β 2 AR, ICL1-9 promoted EGFR transactivation, as monitored by receptor phosphorylation at EGFR Tyr 845 , comparable to what is observed with carvedilol (Fig.…”

Section: Icl1-9supporting

confidence: 56%

β-arrestin–biased signaling through the β ₂ -adrenergic receptor promotes cardiomyocyte contraction

Carr

Schilling

Song

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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100

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β-adrenergic receptors (βARs) are critical regulators of acute cardiovascular physiology. In response to elevated catecholamine stimulation during development of congestive heart failure (CHF), chronic activation of G s -dependent β 1 AR and G i -dependent β 2 AR pathways leads to enhanced cardiomyocyte death, reduced β 1 AR expression, and decreased inotropic reserve. β-blockers act to block excessive catecholamine stimulation of βARs to decrease cellular apoptotic signaling and normalize β 1 AR expression and inotropy. Whereas these actions reduce cardiac remodeling and mortality outcomes, the effects are not sustained. Converse to G-protein-dependent signaling, β-arrestin-dependent signaling promotes cardiomyocyte survival. Given that β 2 AR expression is unaltered in CHF, a β-arrestin-biased agonist that operates through the β 2 AR represents a potentially useful therapeutic approach. Carvedilol, a currently prescribed nonselective β-blocker, has been classified as a β-arrestin-biased agonist that can inhibit basal signaling from βARs and also stimulate cell survival signaling pathways. To understand the relative contribution of β-arrestin bias to the efficacy of select β-blockers, a specific β-arrestin-biased pepducin for the β 2 AR, intracellular loop (ICL)1-9, was used to decouple β-arrestin-biased signaling from occupation of the orthosteric ligand-binding pocket. With similar efficacy to carvedilol, ICL1-9 was able to promote β 2 AR phosphorylation, β-arrestin recruitment, β 2 AR internalization, and β-arrestin-biased signaling. Interestingly, ICL1-9 was also able to induce β 2 AR-and β-arrestin-dependent and Ca 2+ -independent contractility in primary adult murine cardiomyocytes, whereas carvedilol had no efficacy. Thus, ICL1-9 is an effective tool to access a pharmacological profile stimulating cardioprotective signaling and inotropic effects through the β 2 AR and serves as a model for the next generation of cardiovascular drug development.B eta-antagonists, also known as β-blockers, have been indicated for the treatment of pathological cardiac diseases, including congestive heart failure (CHF) and high blood pressure, for decades (1, 2). A select number of these agents, including the clinically used carvedilol, have been identified as β-arrestinbiased agonists of β-adrenergic receptors based on their ability to promote β-arrestin-dependent signaling over G-protein activation (3, 4). It is believed that the β-arrestin activation may provide additional cardioprotection based on its ability to mediate antiapoptotic signaling. As these are orthosteric ligands, there have been no means to decouple the activation of receptor-dependent β-arrestin signaling from the occupation of the orthosteric ligandbinding pocket to study their independent contribution to its efficacy as these properties appear inherently linked.Recently, we described the characterization of a library of modulators of the β 2 -adrenergic receptor (β 2 AR) known as pepducins (5). Pepducins are lipidated peptides derived from the intracel...

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Section: Icl1-9supporting

confidence: 56%

β-arrestin–biased signaling through the β ₂ -adrenergic receptor promotes cardiomyocyte contraction

Carr

Schilling

Song

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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100

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“…Our current results with the ␤ 2 -AR Ϫ/Ϫ mice rule out biased agonism as the explanation because these mice lack a functional ␤ 2 -AR gene and are incapable of producing any ␤ 2 -AR signaling through any pathway. Further support for this is that we have shown that the biased agonist carvedilol, a drug capable of activating the ERK1/2 pathway and EGFR transactivation, but an inverse agonist at the classical G s pathway, was not as effective at reducing AHR as nadolol, an inverse agonist that did not activate ERK1/2 or produce EGFR transactivation (15,17,18).…”

Section: Discussionmentioning

confidence: 84%

“…Thus, inverse agonists inhibit all signaling through the receptor's classical signaling pathway. However, it has recently been shown that many inverse agonists are also capable of activating receptor signaling through alternative pathways (17)(18)(19). For example, many ␤-AR inverse agonists are capable of stimulating a G protein-independent, ␤-arrestindependent activation of ERK1/2 (17).…”

mentioning

confidence: 99%

“…Specifically, we compared the effect of antigen challenge on ␤ 2 -AR Ϫ/Ϫ and wild-type mice to determine airway function, the degree of mucous metaplasia by airway epithelial cells, and the number of inflammatory cells in bronchoalveolar lavage fluid (BALF). These experiments were designed to determine whether the beneficial effects of chronic inverse agonist treatment in the murine asthma model are caused by diminished ␤ 2 -AR signaling or by certain inverse agonists activating alternative pathways to the classical ␤ 2 -AR-G s cascade (i.e., producing ''biased agonism'') (17)(18)(19). The results of these experiments indicate that it is inhibition of all ␤ 2 -AR signaling, and not biased agonism, that is responsible for the beneficial effects of chronic inverse agonist treatment.…”

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confidence: 99%

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β ₂ -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

Nguyen¹,

Lin²,

Parra³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

104

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Chronic regular use of ␤2-adrenoceptor (␤2-AR) agonists in asthma is associated with a loss of disease control and increased risk of death. Conversely, we have found that administration of ␤2-AR inverse agonists results in attenuation of the asthma phenotype in an allergen-driven murine model. Besides antagonizing agonistinduced signaling and reducing signaling by empty receptors, ␤-AR inverse agonists can also activate signaling by novel pathways. To determine the mechanism of the ␤-AR inverse agonists, we compared the asthma phenotype in ␤2-AR-null and wild-type mice. Antigen challenge of ␤2-AR-null mice produced results similar to what was observed with chronic ␤2-AR inverse agonist treatment, namely, reductions in mucous metaplasia, airway hyperresponsiveness (AHR), and inflammatory cells in the lungs. These results indicate that the effects of ␤2-AR inverse agonists are caused by inhibition of ␤2-AR signaling rather than by the induction of novel signaling pathways. Chronic administration of alprenolol, a ␤-blocker without inverse agonist properties, did not attenuate the asthma phenotype, suggesting that it is signaling by empty receptors, rather than agonist-induced ␤2-AR signaling, that supports the asthma phenotype. In conclusion, our results demonstrate that, in a murine model of asthma, ␤2-AR signaling is required for the full development of three cardinal features of asthma: mucous metaplasia, AHR, and the presence of inflammatory cells in the lungs.airway hyperresponsiveness ͉ ␤-blocker ͉ inverse agonist ͉ mucous metaplasia ͉ inflammation

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“…Inhibition of this signalling path promoted myocyte apoptosis. A G protein-independent process of EGFR transactivation may also occur with some β-blockers (e.g., alprenolol, carvedilol) in non-cardiac models (Kim et al, 2008), with these agents also known to protect against acute or long-term effects of myocardial I-R. Grisanti et al (2014) more recently identified EGFR involvement in compartment-specific signalling responses to the -agonist isoproterenol.…”

Section: Role Of the Egfr In Gpcr-triggered Cardioprotectionmentioning

confidence: 99%

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

Reichelt

O’Brien

Thomas

et al. 2017

The International Journal of Biochemistry & Cell Biology

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β-Blockers alprenolol and carvedilol stimulate β-arrestin-mediated EGFR transactivation

Cited by 239 publications

References 44 publications

β-arrestin–biased signaling through the β ₂ -adrenergic receptor promotes cardiomyocyte contraction

β-arrestin–biased signaling through the β ₂ -adrenergic receptor promotes cardiomyocyte contraction

β ₂ -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

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β-Blockers alprenolol and carvedilol stimulate β-arrestin-mediated EGFR transactivation

Cited by 239 publications

References 44 publications

β-arrestin–biased signaling through the β 2 -adrenergic receptor promotes cardiomyocyte contraction

β-arrestin–biased signaling through the β 2 -adrenergic receptor promotes cardiomyocyte contraction

β 2 -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

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β-arrestin–biased signaling through the β ₂ -adrenergic receptor promotes cardiomyocyte contraction

β-arrestin–biased signaling through the β ₂ -adrenergic receptor promotes cardiomyocyte contraction

β ₂ -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model