Comparison of human ETA and ETB receptor signalling via G-protein and β-arrestin pathways

Maguire, Janet J.; Kuc, Rhoda E.; Pell, Victoria R.; Green, Andrew; Brown, Mike; Kumar, Sanj; Wehrman, Tom S.; Quinn, Elizabeth R.; Davenport, Anthony P.

doi:10.1016/j.lfs.2012.03.021

Cited by 28 publications

(27 citation statements)

References 47 publications

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“…In human blood vessels that express predominantly ET A receptors bosentan exhibited, as expected, 2–20 fold higher affinity than in heart with K D of 32 nM in saphenous vein [16] and 3 nM in coronary artery [17]. In contrast bosentan was a much less effective antagonist than would be predicted from its binding affinity in both ET A mediated vasoconstriction in human saphenous vein and coronary artery [15], in ET B mediated smooth muscle contraction [14] and ET B β-arrestin recruitment experiments [10] with a functional affinity of about 2 μM in all these assays. Unexpectedly, in the ET A mediated β-arrestin assay bosentan was 200 fold more effective an antagonist with K B of 10 nM [10] suggesting that bosentan is an ET A β-arrestin biased antagonist.…”

Section: Do Et Receptor Antagonists Show Pathway Bias?supporting

confidence: 56%

“…We have previously published data on both the potency and efficacy of endothelin peptides and sarafotoxins as constrictors of human saphenous vein [9] and in β-arrestin recruitment assays [10]. These data highlighted differences in the relative potencies and efficacies of these agonists in the ET A mediated constrictor and β-arrestin recruitment assays indicative of bias.…”

Section: Calculating Ligand Bias For the Endogenous Et Peptides And Rmentioning

confidence: 98%

“…For the cardiovascular ET A receptor the most appropriate reference ligand is ET-1. All data are expressed as a % of the maximum ET-1 response and analysed as described [10], to obtain values of log 10 (τ/KA) that are used for subsequent determination of bias factors. Fig.…”

Section: Calculating Ligand Bias For the Endogenous Et Peptides And Rmentioning

confidence: 99%

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Evidence for biased agonists and antagonists at the endothelin receptors

Maguire

2016

Life Sciences

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Biased ligands represent a new strategy for the development of more effective and better tolerated drugs. To date there has been a paucity of research exploring the potential of ligands that exhibit either G protein or β-arrestin pathway selectivity at the endothelin receptors. Re-analysis of data may allow researchers to determine whether there is existing evidence that the endogenous ET peptides or currently available agonists and antagonists exhibit pathway bias in a particular physiological or disease setting and this is explored in the review. An alternative to molecules that bind at the orthosteric site of the ET receptors are cell penetrating peptides that interact with a segment of an intracellular loop of the receptor to modify signalling behaviour. One such peptide IC2B has been shown to have efficacy in a model of pulmonary arterial hypertension. Finally, understanding the molecular pathways that contribute to disease is critical to determining whether biased ligands will provide clinical benefit. The role of ETA signalling in ovarian cancer has been delineated in some detail and this has led to the suggestion that the development of ETA G protein biased agonists or β-arrestin biased antagonists should be explored.

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Section: Do Et Receptor Antagonists Show Pathway Bias?supporting

confidence: 56%

Section: Calculating Ligand Bias For the Endogenous Et Peptides And Rmentioning

confidence: 98%

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Evidence for biased agonists and antagonists at the endothelin receptors

Maguire

2016

Life Sciences

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“…To improve the use of these antagonists in cancer treatment, it is important to focus on the the ability of some ligands, referred to as biased ligands, to selectively trigger G protein-and ␤-arr1-mediated signaling pathways, raising the possibility of selective induction of a subset of signaling pathways (18). This characteristic opens the opportunity of manipulating ET-1 therapeutics to achieve selective inhibition of oncogenic pathways.…”

Section: ␤-Arrestin As Critical Tranducer Of Et-1 Signalingmentioning

confidence: 99%

Endothelin therapeutics in cancer: Where are we?

Rosanò¹,

Bagnato²

2016

American Journal of Physiology-Regulatory, Integrative and Comp

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In human cancers, the autocrine and paracrine loop mediated by the aberrantly activation of endothelin-1 (ET-1) receptor (ET-1R) elicits pleiotropic effects, preferentially mediated by the scaffold protein ␤-arrestin 1 (␤-arr1), on tumor cells and on the host microenvironment, providing a strong rationale for targeting ET-1 receptors. This review describes the most up-to-date preclinical and clinical results obtained by using ET-1 therapeutics. The previous negative clinical results of ET-1 therapeutics should not prevent us from setting the standard of this class of drugs for future well-designed clinical trials. The preclinical data obtained with the dual ET AR and ETBR antagonist macitentan indicate that this molecule, which targets cancer cells and tumor-associated microenvironmental elements, could be a cancer therapeutic option. The field of ET-1 therapeutics will be improved in the next decade, facilitated by the new knowledge on the genomic landscape of the human stroma and tumor, and by the low invasive approaches based on liquid biopsies for the discovery of predictive biomarkers. The information obtained from preclinical studies in patient-derived models and from the Cancer Genome Atlas will set the scene of precision medicine for cancer. Results from these studies are expected to open the possibility that ET-1R antagonists might be more efficacious as molecular cancer therapeutics, able to hamper the functional ␤-arr1-dependent signaling complexes, either alone or coupled with new targeted approaches.␤-arrestin; cancer; endothelin-1; endothelin-1 receptor; target therapy RECENT INVESTIGATIONS have consistently suggested that endothelin-1 (ET-1), a small bioactive peptide of 21 residues derived from longer prepro-ET-1 precursor, is an important signal messenger in different pathological conditions, including human cancers (24,35). ET-1 belongs to a family of closely related peptides that include ET-2 and ET-3, which are all similar in structure to ET-1, but are separate gene products, with tissue-specific expression. ETs act mainly via G protein-coupled receptors (GPCR) from endothelin receptor type A (ET A R) and B (ET B R) (24). The two receptors can be differentiated by agonists and antagonists binding affinity and in their cellular distributions. The ET A R binds ET-1 with the greatest affinity, whereas ET-1, ET-2, and ET-3 all have equal affinity for the ET B R.It is now well known that ET-1 receptors can activate several signaling pathways in a G protein-independent manner via complexes with ␤-arrestin (␤-arr)-1 or -2 (18, 24). The scaffold protein ␤-arr1 serves as a copilot in ET-1 signaling to organize complex networks driving tumor progression (7,23,25,26,28,30,33). Thus ET-1 axis confers pleiotropic effects on both tumor cells and microenvironment, modulating different processes by activating ␤-arr-mediated pathways (Fig. 1A). A lesson learned from various tumor models is that there are different expression profiles of the ET-1 receptors compared with normal tissues. There are cancers expres...

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“…Given its much higher affinity for the ET A R (selective antagonist; ET A R K i = 0.28 6 0.23 nM, ET B R K i = 250 6 50 nM in human muscle cells) (Maguire et al, 2012), the theoretical concept arose that a better clinical outcome was achieved by conserving the potentially beneficial effects of stimulation of the ET B R, clearance of ET-1, and vasodilation. Its efficacy in the treatment of pulmonary arterial hypertension was first shown in a trial with 64 patients (Galié et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Endothelin Receptor B Protects Granulocyte Macrophage Colony-Stimulating Factor mRNA from Degradation

Jungck

Knobloch

Körber

et al. 2015

J Pharmacol Exp Ther

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Evidence is lacking on the differential effects of the two therapeutic concepts of endothelin receptor antagonists (ERAs): the blockade of only the endothelin receptor A (ET A R; selective antagonism) versus both ET A R and endothelin receptor B (ET B R; dual blockade). Ambrisentan, a selective ERA, and bosentan, a dual blocker, are both available for therapy. We hypothesized that there are differences in the potential of ERAs to ameliorate inflammatory processes in human airway smooth muscle cells (HASMCs) and aimed to unravel underlying mechanisms. We used HASMC culture, enzyme-linked immunosorbent assay, and quantitative reversetranscription polymerase chain reaction. Tumor necrosis factor a (TNFa) induced transcription and expression of chemokine (C-X-C motif) ligand 2 (CXCL2), chemokine (C-X-C motif) ligand 3 (CXCL3), granulocyte macrophage colony-stimulating factor (GM-CSF), and matrix metalloproteinase 12 (MMP12) in HASMCs. In concentrationresponse experiments, bosentan led to a significantly greater reduction of GM-CSF and MMP12 protein release than ambrisentan, whereas there was no significant difference in their effect on GM-CSF and MMP12 mRNA. Both ERAs reduced CXCL3 protein and mRNA equally but had no effect on CXCL2. Blocking mitogen-activated protein kinases revealed that both ET A R and ET B R signal through p38 mitogen-activated protein kinase, but ET B R also signals through extracellular signal-regulated kinase (ERK) 1/2 to induce GM-CSF expression. In the presence of the transcription inhibitor actinomycin D, bosentan, but not ambrisentan, reduced GM-CSF but not MMP12 or CXCL3 mRNA. In conclusion, blockade of each endothelin receptor subtype reduces GM-CSF transcription, but blocking ET B R additionally protects GM-CSF mRNA from degradation via ERK-1/2. Accordingly, blocking both ET A R and ET B R leads to a stronger reduction of TNFa-induced GM-CSF protein expression. This mechanism might be specific to GM-CSF. Our data stress the anti-inflammatory potential of ERA and warrant further investigation of their utility in chronic inflammatory airway diseases.

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Comparison of human ETA and ETB receptor signalling via G-protein and β-arrestin pathways

Abstract: These data suggest that the pharmacology of ET(A) and ET(B) receptors linked to G-protein- and β-arrestin mediated responses was different and bosentan appeared to show bias, preferentially blocking ET(A) mediated β-arrestin recruitment.

Cited by 28 publications

References 47 publications

Evidence for biased agonists and antagonists at the endothelin receptors

Evidence for biased agonists and antagonists at the endothelin receptors

Endothelin therapeutics in cancer: Where are we?

Endothelin Receptor B Protects Granulocyte Macrophage Colony-Stimulating Factor mRNA from Degradation

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