Selectively Engaging β-Arrestins at the Angiotensin II Type 1 Receptor Reduces Blood Pressure and Increases Cardiac Performance

Violin, Jonathan D.; DeWire, Scott M.; Yamashita, Dennis S.; Rominger, David H.; Nguyen, Lisa; Schiller, Kevin; Whalen, Erin J.; Gowen, Maxine; Lark, Michael W.

doi:10.1124/jpet.110.173005

Cited by 330 publications

(358 citation statements)

References 34 publications

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“…A doseresponse experiment was also performed (Fig. 7f) with varying angiotensin II concentrations at a fixed time point (10 min) and the obtained EC50 of 1.39 nM agrees well with data measuring EC50 values of angiotensin II on other downstream signalling events 37 . Pretreatment of cells with the ROCK inhibitor Y27632 enhanced the BRET signal above baseline levels ( þ 37 mBRET) and abolished the time-dependent decrease in BRET following angiotensin II stimulation (Fig.…”

Section: Establishment and Validation Of The Rluc-pten-yfp Biosensorsupporting

confidence: 65%

A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

et al. 2014

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Tumour suppressor PTEN is a phosphatase that negatively regulates the PI3K/AKT pathway. The ability to directly monitor PTEN conformation and function in a rapid, sensitive manner is a key step towards developing anti-cancer drugs aimed at enhancing or restoring PTEN-dependent pathways. Here we developed an intramolecular bioluminescence resonance energy transfer (BRET)-based biosensor, capable of detecting signal-dependent PTEN conformational changes in live cells. The biosensor retains intrinsic properties of PTEN, enabling structure-function and kinetic analyses. BRET shifts, indicating conformational change, were detected following mutations that disrupt intramolecular PTEN interactions, promoting plasma membrane targeting and also following physiological PTEN activation. Using the biosensor as a reporter, we uncovered PTEN activation by several G proteincoupled receptors, previously unknown as PTEN regulators. Trastuzumab, used to treat ERBB2-overexpressing breast cancers also elicited activation-associated PTEN conformational rearrangement. We propose the biosensor can be used to identify pathways regulating PTEN or molecules that enhance its anti-tumour activity.

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Section: Establishment and Validation Of The Rluc-pten-yfp Biosensorsupporting

confidence: 65%

A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

et al. 2014

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“…promote cardiomyocyte contraction along with activation of antiapoptotic signaling (37,38). To date, a comparable ligand has not been reported for β-adrenergic receptors.…”

Section: Discussionmentioning

confidence: 99%

“…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). Indeed, a β-arrestin-biased agonist for the angiotensin II type 1A receptor (AT1 A R), TRV027, has demonstrated the ability to promote β-arrestin-dependent cardiac contraction in vivo and is currently in clinical trials for the treatment of heart failure (37, 38).…”

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.

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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“…3. The de-emphasis of a debilitating cellular signal and the blockade of the ability of the natural agonist to produce the same signal, such as TRV120027 [Sar-Arg-Val-TyrIle-His-Pro-D-Ala-OH] blockade of angiotensin-mediated vasoconstriction in heart failure with concomitant preservation of angiotensin-mediated b-arrestin signaling (Violin et al, 2006(Violin et al, , 2010.…”

Section: Therapeutic Applications Of Signaling Biasmentioning

confidence: 99%

The Effective Application of Biased Signaling to New Drug Discovery

Kenakin

2015

Mol Pharmacol

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The ability of agonists to selectively activate some but not all signaling pathways linked to pleiotropically signaling receptors has opened the possibility of obtaining molecules that emphasize beneficial signals, de-emphasize harmful signals, and concomitantly deemphasize harmful signals while blocking the harmful signals produced by endogenous agonists. The detection and quantification of biased effects is straightforward, but two important factors should be considered in the evaluation of biased effects in drug discovery. The first is that efficacy, and not bias, determines whether a given agonist signal will be observed; bias only dictates the relative concentrations at which agonist signals will appear when they do appear. Therefore, a Cartesian coordinate system plotting relative efficacy (on a scale of Log relative Intrinsic Activities) as the ordinates and Log(bias) as the abscissae is proposed as a useful tool in evaluating possible biased molecules for progression in discovery programs. Second, it should be considered that the current scales quantifying bias limit this property to the allosteric vector (ligand/receptor/coupling protein complex) and that whole-cell processing of this signal can completely change measured bias from in vitro predictions.

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Selectively Engaging β-Arrestins at the Angiotensin II Type 1 Receptor Reduces Blood Pressure and Increases Cardiac Performance

Cited by 330 publications

References 34 publications

A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

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

The Effective Application of Biased Signaling to New Drug Discovery

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Selectively Engaging β-Arrestins at the Angiotensin II Type 1 Receptor Reduces Blood Pressure and Increases Cardiac Performance

Cited by 330 publications

References 34 publications

A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

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

The Effective Application of Biased Signaling to New Drug Discovery

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Product

Resources

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