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

Abstract

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...

β-Arrestin2 Inhibits Expression of Inflammatory Cytokines in BEAS-2B Lung Epithelial Cells Treated with Cigarette Smoke Condensate via Inhibition of Autophagy

“…Propranolol, as a non-selective beta-blocker, blocks the β-adrenoceptor signaling pathway which is coupled to a G-protein ,but prefers to activate the β-arrestin dependent signaling pathway which is independent of G protein. This mechanism is similar to that seen with the non-selective betablocker/alpha-1 blocker, carvedilol, and the selective β2 adrenergic receptor antagonist, ICI118551 [10,16].…”

Insulin and β Adrenergic Receptor Signaling: Crosstalk in Heart

“…However, the cardiac β 2 AR-G i -Akt signaling is traditionally considered beneficial to myocardium relative to cardiac toxicity induced by β 1 AR signaling [27]. β 2 AR agonist promotes Akt activity to protect against myocyte apoptosis induced by oxidative stress or overactivated β 1 AR signaling in I/R [84–86]. Meanwhile, stimulation of β 2 AR with formoterol also activates eNOS and augments NO bioavailability, which attenuates myocardial cell death after I/R [87].…”

“…The β 2 AR-G i signaling pathway plays a crucial role in the regulation of cell proliferation and protection against cardiomyocyte apoptosis via transactivation of a PI3K-Akt signaling pathway. The β 2 AR-G i signaling pathway also attenuates the βAR-G s -mediated inotropic response via inhibition of AC activity [86]. Meanwhile, adrenergic signaling also activates PKA and Akt to promote glucose uptake in heart[10, 11].…”

Cardiac GPCR–Mediated EGFR Transactivation: Impact and Therapeutic Implications

“…Both βAR isoforms rely on G protein-independent, GRK/βarr-dependent signaling to promote Src- and MMP-mediated HB-EGF shedding and subsequent EGFR activation 15, 16, 39, 64 . In addition, PI3K-dependent Src activation is required for β2AR-mediated EGFR transactivation and significantly increases their association in a multi-receptor complex 44 .…”

“…The orthosteric non-selective β-blocker carvedilol has been shown to induce βarr-biased βAR-mediated signaling, including EGFR transactivation 68–70 ; however, these studies were performed either in HEK 293 cell systems with exogenous receptor expression or in whole heart using a very high dose of carvedilol with no functional insight at a contractile level. Indeed, it has recently been demonstrated that carvedilol does not enhance cardiomyocyte contractility 64 , likely due to its inverse agonist properties 71 . Further, a recent meta-analysis revealed a lack of clinical difference between carvedilol versus the unbiased β-blocker metoprolol succinate in HF patients 72 .…”