β-Adrenergic receptor subtype signaling in heart: From bench to bedside

Woo, Anthony Yiu-Ho; Xiao, Rui‐Ping

doi:10.1038/aps.2011.201

Cited by 151 publications

(112 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, each receptor subtype demonstrates distinct intracellular signaling pathways in the cardiomyocyte. Thus, in the failing heart, the changes in receptor subtype ratio can completely alter the intracellular signaling environment and regulatory crosstalk between the two pathways (34). As currently indicated CHF drugs are either β 1 AR-selective or nonselective agents, the β 2 AR may be an underappreciated therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

“…It is believed that β-blockers act to inhibit pathogenic βAR signaling pathways, including those mediating cell death (31)(32)(33). As G-protein-dependent signaling has been attributed to cardiomyocyte death, the use of a β-arrestin-biased agonist could be an advantageous therapeutic approach (34). Beyond its inability to activate G-protein signaling, evidence has suggested that β-arrestinbiased signaling promotes cardiomyocyte survival signaling along with induction of cardiomyocyte contractility (3,(35)(36)(37)(38).…”

Section: Icl1-9mentioning

confidence: 99%

See 1 more Smart Citation

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.

103

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Icl1-9mentioning

confidence: 99%

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.

103

View full text Add to dashboard Cite

show abstract

“…The functions of NE and E are primarily mediated by the activation of adrenergic receptors (ARs) including α-ARs and β-ARs (9). There are 3 subtypes of β-ARs, specifically β 1 -AR, β 2 -AR and β 3 -AR, which have been identified to date (10). β 1 -ARs and β 2 -ARs are widely expressed in the majority of mammalian cell types, while β 3 -ARs are almost exclusively expressed in adipocytes that have seldom been studied (11).…”

Section: Introductionmentioning

confidence: 99%

Activation of β-adrenergic receptor promotes cellular proliferation in human glioblastoma

Zhang

Liu

et al. 2017

Oncology Letters

View full text Add to dashboard Cite

Abstract. Glioblastoma multiforme is the most common and aggressive form of primary malignant brain tumor. Previous evidence demonstrates that β-adrenergic receptors (β-ARs) are closely associated with the occurrence and development of brain tumors. However, the functional role of β-ARs in human glioblastoma and the underlying mechanisms are not fully understood. In the present study, by using the MTT assay, western blotting, and the reverse transcription polymerase chain reaction, it was revealed that isoproterenol (ISO), an agonist of β-ARs, promoted the proliferation of U251 cells but not U87-MG cells, and that this effect was blocked by the β-ARs antagonist propranolol. It was also demonstrated that ISO transiently induced extracellular signal-related kinase 1/2 (ERK1/2) phosphorylation, and that blocking the mitogen-activated protein kinase pathway by U0126 inhibited ERK1/2 phosphorylation and suppressed U251 cell proliferation. In addition, β-ARs activation increased the expression of matrix metalloproteinase (MMP) family members MMP-2 and MMP-9 mRNA through ERK1/2 activation. In conclusion, these data suggest that β-ARs induce ERK1/2 phosphorylation, which may in turn increase MMPs expression to promote U251 cell proliferation. These results provide additional insight into the specific roles of β-ARs in glioblastoma.

show abstract

“…In the heart, ␤AR stimulation generates an increase in inotropy and chronotropy (25). Research into the effects of ␤AR stimulation on skeletal muscle contraction has yet to reach a consensus; results in this tissue seem to vary based upon species, muscle type, and even dose of agonist (17).…”

Section: Grk2 and Skeletal Muscle Physiologymentioning

confidence: 99%

Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy

Woodall

Luongo

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

GRK2, a G protein-coupled receptor kinase, plays a critical role in cardiac physiology. Adrenergic receptors are the primary target for GRK2 activity in the heart; phosphorylation by GRK2 leads to desensitization of these receptors. As such, levels of GRK2 activity in the heart directly correlate with cardiac contractile function. Furthermore, increased expression of GRK2 after cardiac insult exacerbates injury and speeds progression to heart failure. Despite the importance of this kinase in both the physiology and pathophysiology of the heart, relatively little is known about the role of GRK2 in skeletal muscle function and disease. In this study we generated a novel skeletal muscle-specific GRK2 knock-out (KO) mouse (MLC-Cre:GRK2 fl/fl ) to gain a better understanding of the role of GRK2 in skeletal muscle physiology. In isolated muscle mechanics testing, GRK2 ablation caused a significant decrease in the specific force of contraction of the fast-twitch extensor digitorum longus muscle yet had no effect on the slow-twitch soleus muscle. Despite these effects in isolated muscle, exercise capacity was not altered in MLC-Cre:GRK2 fl/fl mice compared with wild-type controls. Skeletal muscle hypertrophy stimulated by clenbuterol, a ␤ 2 -adrenergic receptor (␤ 2 AR) agonist, was significantly enhanced in MLC-Cre:GRK2 fl/fl mice; mechanistically, this seems to be due to increased clenbuterol-stimulated pro-hypertrophic Akt signaling in the GRK2 KO skeletal muscle. In summary, our study provides the first insights into the role of GRK2 in skeletal muscle physiology and points to a role for GRK2 as a modulator of contractile properties in skeletal muscle as well as ␤ 2 AR-induced hypertrophy. G protein-coupled receptors (GPCRs)2 comprise the largest family of membrane proteins in the genome. GPCRs regulate diverse processes throughout the body by responding to a vast array of extracellular stimuli including hormones, neurotransmitters, and photons of light (1). Equally important to the stimulation and activation of GPCRs is the desensitization and "shutting-off" of the receptor. This task is primarily conducted by the GPCR kinase (GRK) family of proteins (2, 3). GRK2 is ubiquitously expressed throughout the tissues of the body, perhaps most notably in the heart where its regulation of adrenergic receptors (ARs) is critical to physiological heart function. Cardiac overexpression of GRK2 in mice suppresses contractility, whereas cardiac overexpression of the GRK2 inhibitor ␤ARKct (a C-terminal peptide that competes with GRK2 binding to G ␤␥ ) enhances contractile function (4). Catecholamine overdrive during heart failure drives increased GRK2 expression in the cardiomyocyte, ultimately leading to excessive desensitization of ␤ARs, loss of receptor density, and a drop in inotropic reserve (5-7). Indeed, myocardial inhibition or deletion of GRK2 can prevent and even reverse heart failure in numerous animal models (4, 8 -13).Although we have a firm understanding of the role of GRK2 in the physiology and pathophysiology of t...

show abstract

β-Adrenergic receptor subtype signaling in heart: From bench to bedside

Cited by 151 publications

References 93 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

Activation of β-adrenergic receptor promotes cellular proliferation in human glioblastoma

Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy

Contact Info

Product

Resources

About

β-Adrenergic receptor subtype signaling in heart: From bench to bedside

Cited by 151 publications

References 93 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

Activation of β-adrenergic receptor promotes cellular proliferation in human glioblastoma

Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy

Contact Info

Product

Resources

About

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