Molecular structure and mechanisms of action of mammalian angiotensin II receptors

Clauser, Éric; Curnow, Kathleen M.; Conchon, Sophie; Davies, Eleanor; Teutsch, B; Vianello, Barbara; Monnot, Catherine; Corvol, Pierre

doi:10.1097/00060793-199510000-00006

Cited by 14 publications

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“…The major signaling events following agonist binding to this receptor are activation of phospholipase C via a Gq protein, mobilization of the calcium intracellular stores, and activation of protein kinase C. MAP kinase and Jak/STAT pathways are also activated and may participate in the hypertrophic actions of Ang II (1). There are 2 AT 1 subtypes in rodents, AT 1A and AT 1B (2,3); the tissue distribution of the 2 subtypes (4) and knockout experiments in mice (5-7) indicate that cardiovascular, renal, and adrenal actions of Ang II are mainly mediated by AT 1A .…”

Section: Introductionmentioning

confidence: 99%

“…Several human genetic diseases appear to be consequences of such GPCR gain-of-function mutant expression (11,12). Therefore, it was logical to investigate whether cases of human hypertension are associated with such activating mutations of AT 1 . However, no mutation of AT 1 coding sequence had previously been identified in hypertension or, more particularly, in primary hyperaldosteronism (13,14).…”

Section: Introductionmentioning

confidence: 99%

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Gain-of-function mutant of angiotensin II receptor, type 1A, causes hypertension and cardiovascular fibrosis in mice

Billet¹,

Bardin²,

Verp³

et al. 2007

J. Clin. Invest.

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The role of the renin-angiotensin system has been investigated by overexpression or inactivation of its different genes in animals. However, there is no data concerning the effect of the constitutive activation of any component of the system. A knockin mouse model has been constructed with a gain-of-function mutant of the Ang II receptor, type 1A (AT 1A ), associating a constitutively activating mutation (N111S) with a C-terminal deletion, which impairs receptor internalization and desensitization. In vivo consequences of this mutant receptor expression in homozygous mice recapitulate its in vitro characteristics: the pressor response is more sensitive to Ang II and longer lasting. These mice present with a moderate (~20 mmHg) and stable increase in BP. They also develop early and progressive renal fibrosis and cardiac fibrosis and diastolic dysfunction. However, there was no overt cardiac hypertrophy. The hormonal parameters (lowrenin and inappropriately normal aldosterone productions) mimic those of low-renin human hypertension. This new model reveals that a constitutive activation of AT 1A leads to cardiac and renal fibrosis in spite of a modest effect on BP and will be useful for investigating the role of Ang II in target organs in a model similar to some forms of human hypertension. IntroductionThe Ang II receptor, type 1 (AT 1 ), is a G protein-coupled receptor (GPCR) that transduces the main physiological actions of the renin-angiotensin system (RAS) in target cells. The major signaling events following agonist binding to this receptor are activation of phospholipase C via a Gq protein, mobilization of the calcium intracellular stores, and activation of protein kinase C. MAP kinase and Jak/STAT pathways are also activated and may participate in the hypertrophic actions of Ang II (1). There are 2 AT 1 subtypes in rodents, AT 1A and AT 1B (2, 3); the tissue distribution of the 2 subtypes (4) and knockout experiments in mice (5-7) indicate that cardiovascular, renal, and adrenal actions of Ang II are mainly mediated by AT 1A . The unambiguous role of AT 1 in controlling BP is evidenced in numerous animal models. For example, the knockout of AT 1A in mouse reduces BP (5, 6), and its overexpression by gene duplication increases BP in female mice (8). This role contrasts with the absence of clear involvement of renin angiotensin genes in genetic forms of human hypertension (9).The concept of constitutive activation is an important breakthrough in the understanding of GPCR molecular functions: point mutations stabilize the receptor in an active conformation independent of ligand, resulting in a permanent activation of the

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gain-of-function mutant of angiotensin II receptor, type 1A, causes hypertension and cardiovascular fibrosis in mice

Billet¹,

Bardin²,

Verp³

et al. 2007

J. Clin. Invest.

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“…16 We also showed that supplementation with insulin and administration of pharmacologic doses of losartan could improve cardiac contraction as well as coronary blood flow in the same model, through the Table 3 The calculated kinetic parameters of Ang II binding to its receptors at the coronary endothelium. (1, 3), (1,5), (2,3), (3,4), (3,5), (3,6), (4,5), (5, 6) are significant (p<0.05).…”

Section: Discussionmentioning

confidence: 97%

Cross-talk related to insulin and angiotensin II binding on myocardial remodelling in diabetic rat hearts

Maharsy

Kadi

Issa

et al. 2007

J Renin Angiotensin Aldosterone Syst

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This study focused on the regulation and affinity modulation of angiotensin II (Ang II) binding to its receptor subtypes (AT(1)- and AT(2)-receptor) in the coronary endothelium (CE) and cardiomyocytes (CM) of Sprague-Dawley male rats in normal (N), normal treated with losartan (NL), streptozotocin-induced diabetic (D), insulin-treated diabetic (DI), losartan-treated diabetic (DL), and diabetic co-treated with insulin and losartan (DIL). Heart perfusion was used to estimate Ang II binding affinity (tau=1/k-(n)) to its receptor subtypes on CE and CM. Diabetes decreased tau value on CE and increased it on CM as compared to normal. In DL group, the tau value decreased on CE but was normalised on CM. Insulin treatment alone (DI) or with losartan (DIL) restored t to normal on both CE and CM. Western blot results for AT(1)-receptor density showed an increase in diabetics compared to normal with no normalising effect with insulin treatment. The AT(1)-receptor density was normalised in the diabetic groups treated with losartan +/- insulin. Results for AT(2)-receptor regulation revealed a significant difference between untreated (D) and losartan-treated (DL, DIL) diabetic groups. All of these data show the interrelated pathway and cross-talk between insulin and Ang II system indicating potentially negative effects on the diabetic heart.

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“…[7][8][9] The activation of the receptor is coupled to several intracellular proteins, starting with a G protein. 10 The receptor domains that couple to G proteins involve the second and third cytosolic loops and the proximal segment of the carboxy-terminal domain. 10 -12 In the rat, AT 1A , AT 1B , and AT 2 receptors are located on chromosomes 17, 2, and X, respectively.…”

Section: Ang II Receptorsmentioning

confidence: 99%

Angiotensin II and the Heart

2000

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Abstract-The active end product of the renin-angiotensin system, angiotensin II (Ang II), through the activation of specific Ang II receptors, regulates cardiac contractility, cell coupling, and impulse propagation and is involved in cardiac remodeling, growth, and apoptosis. We review these subjects, as well as the second messengers that are involved, and the synthesis of Ang II in the heart under normal and pathological conditions. Finally, we discuss the possibility that there is an intracrine renin-angiotensin system in the heart that plays a role in the control of cell communication and inward Ca 2ϩ current. (Hypertension. 2000;35:1183-1188.)Key Words: angiotensin Ⅲ heart Ⅲ hypertrophy Ⅲ receptors, angiotensin Ⅲ renin Ⅲ signal transduction A ngiotensin (Ang) II, through the activation of specific Ang II receptors, regulates cardiac contractility, cell communication, and impulse propagation. In addition, Ang II is involved in cardiac remodeling, growth, and apoptosis. In the past 10 years, the concept of a local renin-angiotensin system (RAS) located in the heart and other organs has gradually gained support, particularly with the demonstration that elements of the RAS cascade (ie, renin, angiotensinogen, Ang I, Ang II, and angiotensin-converting enzyme [ACE]) are present in tissues. 1,2 In the present article, we review up-to-date evidence that Ang II receptor activation is related to the different actions of Ang II in the heart. We also discuss renin-and ACE-dependent generation of Ang II at cardiac tissue sites and the evidence that there is an intracrine RAS in the heart. Ang II generation through alternative pathways (eg, through cathepsin D, tonin, or chymase) as well as the cardiac effects of other angiotensin metabolites, eg, Ang III, Ang IV, and Ang-(1-7), and their receptors are outside the scope of this review and will not be discussed. Ang II ReceptorsThe effect of Ang II on cardiac tissue is related to the activation of 2 specific receptors, AT 1 and AT 2 . 3,4 The AT 1 receptor has 2 subtypes: AT 1A and AT 1B . 5 AT 1A receptors are major blood pressure regulators and potent growth stimulators in cardiomyocytes in vivo, whereas AT 1B receptors are involved in the control of vascular tone when AT 1A receptors are absent. 6 Ang II receptors are 7-transmembrane domain receptors whose primary structures have been established by molecular cloning. [7][8][9] The activation of the receptor is coupled to several intracellular proteins, starting with a G protein. 10 The receptor domains that couple to G proteins involve the second and third cytosolic loops and the proximal segment of the carboxy-terminal domain. 10 -12 In the rat, AT 1A , AT 1B , and AT 2 receptors are located on chromosomes 17, 2, and X, respectively. 11 Samyn et al 13 have demonstrated that cardiac AT 1 receptor gene expression is relatively unchanged during fetal and newborn life and that AT 2 receptor mRNA expression is high during fetal development and decreases rapidly after birth. Administration of Ang II to a rat whole embryo c...

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Molecular structure and mechanisms of action of mammalian angiotensin II receptors

Cited by 14 publications

References 0 publications

Gain-of-function mutant of angiotensin II receptor, type 1A, causes hypertension and cardiovascular fibrosis in mice

Gain-of-function mutant of angiotensin II receptor, type 1A, causes hypertension and cardiovascular fibrosis in mice

Cross-talk related to insulin and angiotensin II binding on myocardial remodelling in diabetic rat hearts

Angiotensin II and the Heart

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