Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor

Balakumar, Pitchai; Jagadeesh, Gowraganahalli

doi:10.1530/jme-14-0125

Cited by 67 publications

(66 citation statements)

References 117 publications

(144 reference statements)

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“…Although not directly tested in this study, one possible mechanism where by the AT1-AA can increase ANGII sensitivity is by binding to the 2 nd extracellular loop of the AT1 G-coupled receptor, creating bonds between transmembrane receptor domains 2 and 7, triggering a conformational change that will increase the binding affinity for ANG II 36, 46 . Another mechanism is by dimerization of the AT1R with the vasodepressor bradykinin receptor (B 2 ) 47 .…”

Section: Discussionmentioning

confidence: 99%

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Agonistic Autoantibodies to the Angiotensin II Type 1 Receptor Enhance Angiotensin II–Induced Renal Vascular Sensitivity and Reduce Renal Function During Pregnancy

et al. 2016

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Preeclampsia is a multisystemic disorder that is characterized by new-onset hypertension that usually occurs in the third trimester of pregnancy. 1,2 It is estimated that between 3% and 5% of pregnant women in the United States each year have preeclampsia. Preeclampsia is the leading cause of preterm birth, morbidity, and mortality for the mother and the fetus. 1,2Women with preeclampsia have elevated levels of the angiotensin II type 1 receptor autoantibodies (AT1-AA), oxidative stress, reduced renal function, and increased angiotensin II (ANG II) sensitivity.3-8 AT1-AAs in preeclampsia bind with a high affinity to the 7 amino acid sequence on the second extracellular loop of the AT1 receptor, in which it activates the AT1 receptor, increases intracellular calcium levels, and stimulates activation of intracellular mean arterial pressure/ERK kinase and tumor necrosis factor-α pathways similar to ANG II. [9][10][11][12][13] Several studies from our laboratory and others have demonstrated the important role of AT1-AAs in the pathophysiology of preeclampsia. In vitro studies with vascular smooth muscle and trophoblast cells demonstrate increased tissue factor VII and tissue factor activity, reactive oxygen species (ROS), NADPH oxidase components, and activation of NFκβ when incubated with AT1-AAs.13-15 Furthermore, human umbilical vein endothelial cells incubated for 6 hours with the AT1-AAs drastically increased endothelin-1 protein expression. 16 In vivo studies, in which isolated human and rodent AT1-AAs administered to rats during pregnancy, increased blood pressure, oxidative stress, renal artery resistant index, and several circulating factors associated with preeclampsia, such as soluble fms-like tyrosine kinase 1, sEng, endothelin-1, and endothelial microparticles. 7,[16][17][18][19][20][21][22] Thus, all these studies taken together confirm the critical role of AT1-AAs in causing many of the common characteristics of preeclampsia observed in women. 7,[16][17][18][19][20][21][22] Another characteristic shared by women with preeclampsia is increased sensitivity to ANG II, demonstrated years ago by Gant et al. 8 In Gant et al's 8 studies, young women between ages 13 and 17 years, with majority being black American women, were infused with various doses of ANG II until their diastolic blood pressure increased by 20 mm Hg. 11 In this study, they found that women destined to become preeclamptic displayed an increase in blood pressure at lower concentrations of ANG II versus those who had a normal pregnancy. From this early study, it was established that women with preeclampsia have increased sensitivity to ANG II from as early as 22 weeks of gestation until term. 11Abstract-Preeclamptic women produce agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) and exhibit increased blood pressure (mean arterial pressure), vascular sensitivity to angiotensin II (ANG II), and display a decrease in renal function. The objective of this study was to examine the renal hemodynamic changes during pregnancy i...

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Section: Discussionmentioning

confidence: 99%

“…After this discovery numerous research has been performed, examining the role of AT1-AAs in the pathophysiology of preeclampsia 36–38 . This AT1-AA binds to and activates the AT1R, thereby increasing chronotropic events in cultured cardiomyocytes, very similarly to ANGII.…”

Section: Discussionmentioning

confidence: 99%

Agonistic Autoantibodies to the Angiotensin II Type 1 Receptor Enhance Angiotensin II–Induced Renal Vascular Sensitivity and Reduce Renal Function During Pregnancy

et al. 2016

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“…Angiotensin II (AngII) 5 type 1 receptor (AT 1 R) is a G protein-coupled receptor (GPCR), mainly found in heart, brain, liver, and kidneys, regulating normal blood pressure, as well as fluid and electrolyte homeostasis (1,2). Overstimulation of AT 1 R leads to diseases such as hypertension, cardiovascular hypertrophy, and fibrosis, whereas blocking the activity of AT 1 R lowers blood pressure (3,4).…”

Section: Ecl2mentioning

confidence: 99%

“…Multiple studies suggest that such additional tissue-protective benefits from treatment with ARBs may be mediated by AT 1 R ␤-arrestin signaling, although the structural basis for differential activation of this mechanism by ARBs is unknown (8,10). AngII analogs, such as TRV120027, lacking G protein agonism but activating ␤-arrestin signaling, protect the heart and vasculature in a pathological setting better than common ARBs (2,8,9), suggesting the need for a better understanding of the mechanisms for functional selectivity of different AT 1 R ligands.…”

Section: Ecl2mentioning

confidence: 99%

Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor

Zhang

Ünal

Desnoyer

et al. 2015

Journal of Biological Chemistry

157

194

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Background: Angiotensin receptor (AT 1 R) blockers are critical therapeutics used to treat cardiovascular disease. Results: We solved the AT 1 R-olmesartan structure and identified specific interactions for olmesartan derivatives with different functions. Conclusion: Our results identified residues critical for the binding of different ligands and allosteric modulation by sodium ion. Significance: Our results provide new insights into the structural basis for ligand recognition and functional selectivity at AT 1 R.

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“…The first glimpse into the human AT 1 R crystal structure was recently provided and it was the first step towards that goal[50]. Unfortunately however, that crystal structure lacked the intracellular C-terminal tail of the receptor, which is exactly the AT 1 R region that interacts with βarrs [51]. …”

Section: Implications For At1r Blocker Medicinal Chemistrymentioning

confidence: 99%

Angiotensin receptor blocker drugs and inhibition of adrenal beta-arrestin-1-dependent aldosterone production: Implications for heart failure therapy

Lymperopoulos

Aukszi

2017

WJC

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Aldosterone mediates many of the physiological and pathophysiological/cardio-toxic effects of angiotensin II (AngII). Its synthesis and secretion from the zona glomerulosa cells of the adrenal cortex, elevated in chronic heart failure (HF), is induced by AngII type 1 receptors (AT1Rs). The AT1R is a G protein-coupled receptor, mainly coupling to Gq/11 proteins. However, it can also signal through β-arrestin-1 (βarr1) or -2 (βarr2), both of which mediate G protein-independent signaling. Over the past decade, a second, Gq/11 protein-independent but βarr1-dependent signaling pathway emanating from the adrenocortical AT1R and leading to aldosterone production has become appreciated. Thus, it became apparent that AT1R antagonists that block both pathways equally well are warranted for fully effective aldosterone suppression in HF. This spurred the comparison of all of the currently marketed angiotensin receptor blockers (ARBs, AT1R antagonists or sartans) at blocking activation of the two signaling modes (G protein-, and βarr1-dependent) at the AngII-activated AT1R and hence, at suppression of aldosterone in vitro and in vivo. Although all agents are very potent inhibitors of G protein activation at the AT1R, candesartan and valsartan were uncovered to be the most potent ARBs at blocking βarr activation by AngII and at suppressing aldosterone in vitro and in vivo in post-myocardial infarction HF animals. In contrast, irbesartan and losartan are virtually G protein-“biased” blockers at the human AT1R, with very low efficacy for βarr inhibition and aldosterone suppression. Therefore, candesartan and valsartan (and other, structurally similar compounds) may be the most preferred ARB agents for HF pharmacotherapy, as well as for treatment of other conditions characterized by elevated aldosterone.

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Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor

Cited by 67 publications

References 117 publications

Agonistic Autoantibodies to the Angiotensin II Type 1 Receptor Enhance Angiotensin II–Induced Renal Vascular Sensitivity and Reduce Renal Function During Pregnancy

Agonistic Autoantibodies to the Angiotensin II Type 1 Receptor Enhance Angiotensin II–Induced Renal Vascular Sensitivity and Reduce Renal Function During Pregnancy

Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor

Angiotensin receptor blocker drugs and inhibition of adrenal beta-arrestin-1-dependent aldosterone production: Implications for heart failure therapy

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