Functional Relevance of Biased Signaling at the Angiotensin II Type 1 Receptor

Tilley, Douglas G.

doi:10.2174/187153011795564133

Cited by 16 publications

(7 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SII-induced change in the AT1R conformation is different from that of AngII stimulation (7). Previous reports suggested that SII activates -arrestin signaling without G protein coupling (8). However, it was reported that SII also activates G protein signaling but in a different way from AngII, although the activation by SII is much weaker than AngII (9).…”

Section: Introductionmentioning

confidence: 83%

Ezrin, Radixin, and Moesin Phosphorylation in NIH3T3 Cells Revealed Angiotensin II Type 1 Receptor Cell-Type–Dependent Biased Signaling

2013

View full text Add to dashboard Cite

Abstract. -Arrestin-biased agonists are a new class of drugs with promising therapeutic effects. The molecular mechanisms of -arrestin-biased agonists are still not completely identified. Here, we investigated the effect of angiotensin II (AngII) and [Sar1,Ile4,Ile8] AngII (SII), a -arrestinbiased agonist, on ezrin-radixin-moesin (ERM) phosphorylation in NIH3T3 cells (a fibroblast cell line) stably expressing AngII type 1A receptor. ERM proteins are cross-linkers between the plasma membrane and the actin cytoskeleton and control a number of signaling pathways. We also investigated the role of Gq protein and -arrestins in mediating ERM phosphorylation. We found that AngII stimulates ERM phosphorylation by acting as a -arrestin-biased agonist and AngIIstimulated ERM phosphorylation is mediated by -arrestin2 not -arrestin1. We also found that SII inhibits ERM phosphorylation by acting as a Gq protein-biased agonist. We concluded that ERM phosphorylation is a unique -arrestin-biased agonism signal. Both AngII and SII can activate either Gq protein or -arrestin-mediated signaling as functional biased agonists according to the type of the cell on which they act.

show abstract

Section: Introductionmentioning

confidence: 83%

Ezrin, Radixin, and Moesin Phosphorylation in NIH3T3 Cells Revealed Angiotensin II Type 1 Receptor Cell-Type–Dependent Biased Signaling

2013

View full text Add to dashboard Cite

show abstract

“…34 Src can be activated in a Gαq protein-or β-arrestin2 dependent manner for EGFR transactivation. 35, 36 We recently also confirmed that β-arrestin2-dependent Src activation is a prerequisite for mechanical stretch-induced ERK1/2 phosphorylation. 31 The AT1-R stimulates tyrosine phosphorylation of the Janus family kinases (Jak1, Jak2, Jak3, and Tyk2).…”

Section: Mechanical Stress Activates At1-r Without the Involvement Ofmentioning

confidence: 53%

Insights Into the Activation and Inhibition of Angiotensin II Type 1 Receptor in the Mechanically Loaded Heart

You

Wang

et al. 2014

Circ J

View full text Add to dashboard Cite

“…Specifically, this signalling has been connected to Gαq and Gαi signalling, and can lead to a number of intracellular downstream effects ranging from migration and adhesion to proliferation. ERK is phosphorylated and activated by at least three downstream AT1R signalling pathways, including the protein kinase C (PKC)-dependent pathway, the β-arrestin-dependent pathway, and the epidermal growth factor receptor (EGFR) transactivation pathway [ 11 ]. To assess the role of RGS1 in the Ang II-stimulated activation of the MAPK signalling pathway, we assessed the levels of phosphorylated Erk1/2 protein and other known kinases induced by Ang II, using transient transfections of Rgs1 in the murine vascular smooth muscle cell line (MOVAS).…”

Section: Resultsmentioning

confidence: 99%

Vascular wall regulator of G-protein signalling-1 (RGS-1) is required for angiotensin II–mediated blood pressure control

Patel

Chuaiphichai

Douglas

et al. 2018

Vascular Pharmacology

View full text Add to dashboard Cite

G-Protein coupled receptors (GPCRs) activate intracellular signalling pathways by coupling to heterotrimeric G-proteins that control many physiological processes including blood pressure homeostasis. The Regulator of G-Protein Signalling-1 (RGS1) controls the magnitude and duration of downstream GPCR signalling by acting as a GTPase-activating protein for specific Gα-proteins. RGS1 has contrasting roles in haematopoietic and non-haematopoietic cells. Rgs1−/−ApoE−/− mice are protected from Angiotensin II (Ang II)-induced aortic aneurysm rupture. Conversely, Ang II treatment increases systolic blood pressure to a greater extent in Rgs1−/−ApoE−/− mice than ApoE−/− mice, independent of its role in myeloid cells. However the precise role of RGS1 in hypertension and vascular-derived cells remains unknown. We determined the effects of Rgs1 deletion on vascular function in ApoE−/− mice. Rgs1 deletion led to enhanced vasoconstriction in aortas and mesenteric arteries from ApoE−/− mice in response to phenylephrine (PE) and U46619 respectively. Rgs1 was shown to have a role in the vasculature, with endothelium-dependent vasodilation being impaired, and endothelium-independent dilatation to SNP being enhanced in Rgs1−/−ApoE−/− mesenteric arteries. To address the downstream signalling pathways in vascular smooth muscle cells (VSMCs) in response to Ang II-stimulation, we assessed pErk1/2, pJNK and pp38 MAPK activation in VSMCs transiently transfected with Rgs1. pErk1/2 signalling but not pJNK and pp38 signalling was impaired in the presence of Rgs1. Furthermore, we demonstrated that the enhanced contractile response to PE in Rgs1−/−ApoE−/− aortas was reduced by a MAPK/Erk (MEK) inhibitor and an L-type voltage gated calcium channel antagonist, suggesting that Erk1/2 signalling and calcium influx are major effectors of Rgs1-mediated vascular contractile responses, respectively. These findings indicate RGS1 is a novel regulator of blood pressure homeostasis and highlight RGS1-controlled signalling pathways in the vasculature that may be new drug development targets for hypertension.

show abstract

Functional Relevance of Biased Signaling at the Angiotensin II Type 1 Receptor

Cited by 16 publications

References 86 publications

Ezrin, Radixin, and Moesin Phosphorylation in NIH3T3 Cells Revealed Angiotensin II Type 1 Receptor Cell-Type–Dependent Biased Signaling

Ezrin, Radixin, and Moesin Phosphorylation in NIH3T3 Cells Revealed Angiotensin II Type 1 Receptor Cell-Type–Dependent Biased Signaling

Insights Into the Activation and Inhibition of Angiotensin II Type 1 Receptor in the Mechanically Loaded Heart

Vascular wall regulator of G-protein signalling-1 (RGS-1) is required for angiotensin II–mediated blood pressure control

Contact Info

Product

Resources

About