G-Protein–Coupled Receptor MrgD Is a Receptor for Angiotensin-(1–7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A

Tetzner, Anja; Gebolys, Kinga; Meinert, Christian; Klein, Sabine; Uhlich, Anja; Trebicka, Jonel; Villacañas, Óscar; Walther, Thomas

doi:10.1161/hypertensionaha.116.07572

Cited by 113 publications

(124 citation statements)

References 34 publications

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“…This notion is further emphasized by the recent discovery of MrgD as another novel receptor for Ang- (1-7) regulating the physiological arterial pressure. 9 Physiological relevance of the Ang-(1-7)/AT1-R axis could be, however, questioned given that the affinity/potency of Ang-(1-7) for AT1-R is modest (≈300 nmol/L) and relatively far from plasma concentrations generally described, with significant differences in between rodents (nmol/L) 26,27 or human species (pM). [28][29][30] Nevertheless, despite the RAAS was originally described as a circulating system, it is now widely accepted that a distinct local RAAS does exist in several tissues, 31 thus promoting a close ligand-receptor proximity to ensure an accurate spatiotemporal regulation of RAAS actions similar to that observed for neurotransmitters concentrations in the synaptic cleft after release.…”

Section: Discussionmentioning

confidence: 99%

Cardioprotective Angiotensin-(1–7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor

et al. 2016

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Hyperactivity of the renin–angiotensin–aldosterone system through the angiotensin II (Ang II)/Ang II type 1 receptor (AT1-R) axis constitutes a hallmark of hypertension. Recent findings indicate that only a subset of AT1-R signaling pathways is cardiodeleterious, and their selective inhibition by biased ligands promotes therapeutic benefit. To date, only synthetic biased ligands have been described, and whether natural renin–angiotensin–aldosterone system peptides exhibit functional selectivity at AT1-R remains unknown. In this study, we systematically determined efficacy and potency of Ang II, Ang III, Ang IV, and Ang-(1–7) in AT1-R–expressing HEK293T cells on the activation of cardiodeleterious G-proteins and cardioprotective β-arrestin2. Ang III and Ang IV fully activate similar G-proteins than Ang II, the prototypical AT1-R agonist, despite weaker potency of Ang IV. Interestingly, Ang-(1–7) that binds AT1-R fails to promote G-protein activation but behaves as a competitive antagonist for Ang II/Gi and Ang II/Gq pathways. Conversely, all renin–angiotensin–aldosterone system peptides act as agonists on the AT1-R/β-arrestin2 axis but display biased activities relative to Ang II as indicated by their differences in potency and AT1-R/β-arrestin2 intracellular routing. Importantly, we reveal Ang-(1–7) a known Mas receptor-specific ligand, as an AT1-R–biased agonist, selectively promoting β-arrestin activation while blocking the detrimental Ang II/AT1-R/Gq axis. This original pharmacological profile of Ang-(1–7) at AT1-R, similar to that of synthetic AT1-R–biased agonists, could, in part, contribute to its cardiovascular benefits. Accordingly, in vivo, Ang-(1–7) counteracts the phenylephrine-induced aorta contraction, which was blunted in AT1-R knockout mice. Collectively, these data suggest that Ang-(1–7) natural-biased agonism at AT1-R could fine-tune the physiology of the renin–angiotensin–aldosterone system.

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Section: Discussionmentioning

confidence: 99%

Cardioprotective Angiotensin-(1–7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor

et al. 2016

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“…MrgD leads to an increase in adenylyl cyclase activity, consequently increasing cAMP levels, thereby activating protein kinase A, and leading to cAMP response elementbinding protein phosphorylation. 24 Additionally, it has been shown that alamandine, via the MrgD receptor, can promote the stimulation of eNOS and the subsequent generation of NO, and thereby exerts its vasodilatory and anti-hypertensive actions. 5 The AT2R receptor stimulates various signaling pathways, which can be categorized into 3 broad types: regulation of protein phosphorylation, activation of phospholipases, and regulation of NO/cyclic guanosine monophosphate (cGMP).…”

Section: Discussionmentioning

confidence: 99%

Differences in Cardiovascular Responses to Alamandine in Two-Kidney, One Clip Hypertensive and Normotensive Rats

Javanmardi

Kouhpayeh

et al. 2017

Circ J

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angiotensin II type 1 receptor (AT1R) blockers. These drugs block angiotensin II (Ang II) -the primary active peptide in the RAS, which has many effects on blood vessels, the heart, the brain and the kidneys -from activating AT1R. AT1R is one of the two well-characterized receptors that Ang II activates (in addition to angiotensin II type 2 receptor (AT2R)). 3 Losartan is an angiotensin receptor blocker, 4 which mainly antagonizes AT1R, while PD123319 can block AT2R and Mas-related G protein-coupled receptor D (MrgD) receptors. 5 Recently, numerous researchers have shown that the RAS has additional complex multifunctional peptides, enzymes and receptors. The discovery of the ACE2/angiotensin-(1-7) [Ang-(1-7)]/Mas receptor axis, 6,7 which counterbalances several functions of the ACE/Ang II/AT1R axis, has highlighted the complexity of the RAS. The ACE2/Ang-(1-7)/ Mas receptor axis acts as a counter-regulatory axis. 7 It involves the heptapeptide peptide known as Ang-(1-7), which acts through a G-protein-coupled receptor called Mas. 7 Ang-(1-7) can be hydrolyzed from Ang II by the action of peptidases such as ACE2 and prolyl endopepti-D espite major progress in the research on the pathogenesis and management of hypertension and other aspects of cardiometabolic disease, these conditions underlie a significant number cases of morbidity and mortality due to cardiovascular and chronic kidney disease. It is predicted that there will be an increase in the hypertension prevalence rate in the United States (US). Currently, this condition affects 29% of the population in this country; that is, ~65 million individuals. 1 The significance of the renin-angiotensin system (RAS) in the development of hypertension and cardiovascular disease is well known. 2 Chronic RAS activation is a significant causal factor associated with the gradual malfunction of organs such as blood vessels, the kidneys and the heart. 2 These consequences of RAS activation have encouraged the development of medicines that can deactivate the RAS and thereby prevent the associated pathologies. The first class of drugs aimed at RAS inhibition are known as angiotensin-converting enzyme (ACE1) inhibitors, and they came on the market in the late 1970 s. Background: Alamandine is a newly discovered component of the renin-angiotensin system, which regulates blood pressure. In this study, the effect of alamandine on cardiovascular parameters in two-kidney, one clip (2K1C) hypertensive rats and normotensive rats, and the possible roles of the angiotensin II type 1 receptor (AT1R) and the PD123319-sensitive receptors in mediating this effect was investigated.

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“…These ligands activate the Mrgprs to initiate the signaling cascades coupled to G q/11 and pertussis toxin (PTX)-sensitive G i/o proteins, activation of which mobilizes PTX-insensitsitive intracellular Ca 2+ and PTX-sensitive inhibition of forskolin-induced activation of adenylyl cyclase [43]. There is also evidence that additional receptors, such as AT 2 receptors and MrgD receptors, may be involved in mediating the effects of ANG (1–7) [47,48,171–173]. …”

Section: New Insights Into the Roles And Therapeutic Implications mentioning

confidence: 99%

The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases

Zhang

Zhuo

2017

Pharmacological Research

378

323

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The renin-angiotensin system (RAS) is undisputedly one of the most prominent endocrine (tissue-to-tissue), paracrine (cell-to-cell) and intracrine (intracellular/nuclear) vasoactive systems in the physiological regulation of neural, cardiovascular, blood pressure, and kidney function. The importance of the RAS in the development and pathogenesis of cardiovascular, hypertensive and kidney diseases has now been firmly established in clinical trials and practice using renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, type 1 (AT1) angiotensin II (ANG II) receptor blockers (ARBs), or aldosterone receptor antagonists as major therapeutic drugs. The major mechanisms of actions for these RAS inhibitors or receptor blockers are mediated primarily by blocking the detrimental effects of the classic angiotensinogen/renin/ACE/ANG II/AT1/aldosterone axis. However, the RAS has expanded from this classic axis to include several other complex biochemical and physiological axes, which are derived from the metabolism of this classic axis. Currently, at least five axes of the RAS have been described, with each having its key substrate, enzyme, effector peptide, receptor, and/or downstream signaling pathways. These include the classic angiotensinogen/renin/ACE/ANG II/AT1 receptor, the ANG II/APA/ANG III/AT2/NO/cGMP, the ANG I/ANG II/ACE2/ANG (1–7)/Mas receptor, the prorenin/renin/prorenin receptor (PRR or Atp6ap2)/MAP kinases ERK1/2/V-ATPase, and the ANG III/APN/ANG IV/IRAP/AT4 receptor axes. Since the roles and therapeutic implications of the classic angiotensinogen/renin/ACE/ANG II/AT1 receptor axis have been extensively reviewed, this article will focus primarily on reviewing the roles and therapeutic implications of the vasoprotective axes of the RAS in cardiovascular, hypertensive and kidney diseases.

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G-Protein–Coupled Receptor MrgD Is a Receptor for Angiotensin-(1–7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A

Cited by 113 publications

References 34 publications

Cardioprotective Angiotensin-(1–7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor

Cardioprotective Angiotensin-(1–7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor

Differences in Cardiovascular Responses to Alamandine in Two-Kidney, One Clip Hypertensive and Normotensive Rats

The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases

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