AT1 receptor
target has curated data in GtoImmuPdb
Target id: 34
Nomenclature: AT1 receptor
Family: Angiotensin receptors
Annotation status:
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Contents:
- Gene and Protein Information
- Previous and Unofficial Names
- Database Links
- Selected 3D Structures
- Natural/Endogenous Ligands
- Agonists
- Antagonists
- Immunopharmacology Comments
- Immuno Process Associations
- Transduction Mechanisms
- Tissue Distribution
- Expression Datasets
- Functional Assays
- Physiological Functions
- Physiological Consequences of Altering Gene Expression
- Phenotypes, Alleles and Disease Models
- Clinically-Relevant Mutations and Pathophysiology
- Biologically Significant Variants
- General Comments
- References
- Contributors
- How to cite this page
Gene and Protein Information  |
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| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 359 | 3q21-q25 | AGTR1 | angiotensin II receptor type 1 | 13,29,31,48,103 |
| Mouse | 7 | 359 | 13 16.0 cM | Agtr1a | angiotensin II receptor, type 1a | 139,176 |
| Mouse | 7 | 359 | 3 7.6 cM | Agtr1b | angiotensin II receptor, type 1b | 139,176 |
| Rat | 7 | 359 | 17q12 | Agtr1a | angiotensin II receptor | 69-70,86,113 |
| Rat | 7 | 359 | 2q24 | Agtr1b | angiotensin II receptor | 40,65,69,76,113,137,151,175 |
| Gene and Protein Information Comments | ||||||
| Both rat and mouse have a second gene that codes for the AT1 receptor. | ||||||
| Previous and Unofficial Names |
| AG2S | AT2R1 | AT2R1A | HAT1R | Agtr1 | angiotensin II type-1 receptor | angiotensin II type-1A receptor | angiotensin II type-1B receptor | AT3 | type-1A angiotensin II receptor | type-1B angiotensin II receptor | vascular type-1 angiotensin II receptor | Agtr-1b | Angtr-1b | Angtr-1a | AT1AR | AT1BR | Type-1 angiotensin II receptor | Agtr-1a | angiotensin II receptor, type 1 | angiotensin II receptor, type 1a | angiotensin II receptor, type 1b | angiotensin II receptor |
| Database Links |
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| Specialist databases | |
| GPCRDB | agtr1_human (Hs), agtra_mouse (Mm), agtrb_mouse (Mm), agtrb_rat (Rn), agtra_rat (Rn) |
| Other databases | |
| ChEMBL Target | CHEMBL227 (Hs), CHEMBL329 (Rn), CHEMBL263 (Rn) |
| DrugBank Target | P30556 (Hs) |
| Ensembl Gene | ENSG00000144891 (Hs), ENSMUSG00000054988 (Mm), ENSMUSG00000049115 (Mm), ENSRNOG00000010640 (Rn), ENSRNOG00000018346 (Rn) |
| Entrez Gene | 185 (Hs), 11607 (Mm), 11608 (Mm), 24180 (Rn), 81638 (Rn) |
| Human Protein Atlas | ENSG00000144891 (Hs) |
| KEGG Gene | hsa:185 (Hs), mmu:11607 (Mm), mmu:11608 (Mm), rno:24180 (Rn), rno:81638 (Rn) |
| OMIM | 106165 (Hs) |
| Orphanet | ORPHA138533 (Hs) |
| RefSeq Nucleotide | NM_000685 (Hs), NM_177322 (Mm), NM_175086 (Mm), NM_031009 (Rn), NM_030985 (Rn) |
| RefSeq Protein | NP_000676 (Hs), NP_780295 (Mm), NP_796296 (Mm), NP_112247 (Rn), NP_112271 (Rn) |
| UniProtKB | P30556 (Hs), P29754 (Mm), P29755 (Mm), P29089 (Rn), P25095 (Rn) |
| Wikipedia | AGTR1 (Hs) |
| Selected 3D Structures |
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| Natural/Endogenous Ligands |
| angiotensin A {Sp: Human} |
| angiotensin II {Sp: Human, Mouse, Rat} |
| angiotensin III {Sp: Human, Mouse, Rat} |
| angiotensin IV {Sp: Human, Mouse, Rat} |
Download all structure-activity data for this target as a CSV file 
| Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| View species-specific agonist tables | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Antagonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| View species-specific antagonist tables | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Antagonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| LY301875, LY303336, telmisartan, candesartan, irbesartan, valsartan, EXP3174, azilsartan medoxomil and saprisartan [148-149] are all classed as insurmountable antagonists. Partial agonist: Activate the receptor but have only partial efficacy (less than 50%) at the receptor relative to a full agonist. Insurmountable antagonists: When preincubated on cells/tissues these competitive antagonists cause a full or partial depression of the maximal response induced by an agonist (e.g. Angiotensin II) in a concentration-response curve. The degree of insurmountable inhibition is related to the formation of a slow dissociating receptor-antagonist complex [46,105,159-161]. Selective ligands ([Sar1,Ile4,Ile8]Ang II, [Sar1-Ala8]-Ang II, [Sar1-Ile8]-Ang II, [Sar1-Gly4,Gly8]-Ang II and TRV120027): Produce greater than 80% activation of G-protein-independent signal and less than 20% activation of G-protein-dependent signal. For an overview of AT1R antagonist binding properties see [107]. An overview of AT1R antagonist binding properties is [107]. |
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| Immunopharmacology Comments |
| Accumulating evidence suggests that regulation of the mutually antagonistic angiotensin receptors AT1 and AT2 is essential for maintaining control of inflammation and that an imbalance between these two receptors has pathophysiological potential [144]. |
| Immuno Process Associations | |||||||||||||||
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| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
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Gi/Go family Gq/G11 family |
Adenylate cyclase inhibition Phospholipase C stimulation Calcium channel Phospholipase A2 stimulation Phospholipase D stimulation Other - See Comments |
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Comments:
Other effectors and responses are inositol phosphate turnover, protein kinase C activation and RhoA activation. Other transducers are JAK2 resulting in STAT3 phosphorylation [99].; Src with effectors FAK, GIT1, CamK II, Cas [115,124]; pp60c-src with effector phospholipase C-gamma 1 [67,100]; β-arrestin resulting in MAPK phosphorylation in the cytoplasm; and CARMA3 with effector NF-κB [104]. Like many growth factors, activation of several tyrosine kinases (receptor (EGFR), non-receptor (JAK, Src, Pyk2)) and phosphorylation and activation of several downstream cascades such as mitogen activated protein (MAP kinase) cascade, the JAK-STAT pathway are observed. AT1R activation also lead to ROS production via activation of the NADH-NADPH oxidase pathways, modulation of ion channels, transactivation of EGFR [14,34,38,51,140-141,153,171]. G-protein dependent signalling leads to phosphorylation and nuclear translocation of Elk-1 and MAPK whereas β-arrestin dependent signalling leads to MAPK phosphorylation in the cytoplasm [5,152] but not nuclear translocation. |
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| References: 34 | |
| Tissue Distribution
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| Physiological Consequences of Altering Gene Expression
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| Physiological Consequences of Altering Gene Expression Comments | ||||||||||
| Mice lacking the AT1a receptor have a marked reduction of systolic blood pressure [173]. There is no impairment of development and no major abnormalities of the heart and vascular system in AT1A KO mice but there are mild signs of mesangial expansion and juxtaglomerular cell hypertrophy. The tubuloglomerular feedback loop is undetectable. The lack of AT1a signaling causes structural abnormalities in the renal vascular system and transforms the phenotype of VSMCs into cell proliferation, induces the escape of VSMCs from the circular mechanical integrity, and results in increased synthesis of extracellular matrices [66]. AT1a receptor knockout mice display less left ventricular remodeling and improved survival after myocardial infarction [55]. Deficiency of angiotensin type 1a receptors in adipocytes reduces differentiation and promotes hypertrophy of adipocytes in lean mice [128]. AngII can elicit renal vasoconstriction, albeit attenuated, in AT1A knockout mice [135]. Ischemia-induced angiogenesis was also impaired in in AT1a receptor knockout mice suggesting that AT1 receptor pathway promotes early angiogenesis by supporting inflammatory cell infiltration and angiogenic cytokine expression [138]. Genetic disruption of AT1a receptor improves long-term survival of mice with chronic severe aortic regurgitation (AR). In cases of chronic severe AR, blockade of AT1 receptor attenuates the progression of LV dilatation, hypertrophy and fibrosis, thereby mitigating heart failure and improving long-term survival [114]. AT1a receptor knockout in mice causes polyuria and urine concentration defects by reducing basal vasopressin levels and its receptor signaling proteins in the inner medulla [94]. AT1a receptor deficient mice exhibited reduced angiogenesis and delay in wound healing in angiotensin II type 1a receptor- [84]. AT1a receptor plays an important role in skin wound healing by accelerating keratinocyte and fibroblast migration via heparin-binding epidermal growth factor (EGF)-like growth factor-mediated EGF receptor transactivation [170]. Expression of AT1a receptors in C1 neurons restores the sympathoexcitation to angiotensin in the rostral ventrolateral medulla of AT1a knockout mice [22]. Mice lacking the AT1B receptor do not differ from wild-type. The AT1B receptor has a minor role but may compensate for much of the regulatory action in AT1A deleted rodent. For example, AT1B receptor mediates calcium signaling in vascular smooth muscle cells of AT1A receptor-deficient mice [181]. Animals with both AT1A and AT1B gene deletion have an impaired growth, hypotension and marked abnormalities in renal structures. There is a complete absence of pressor responses to Ang II. Transgenic mice overexpressing the AT1 receptor exhibit a drastic cardiac hypertrophy and die within several days of age. The transgenic rats however appear normal unless there is pressure or volume overload, which elicit a more pronounced hypertrophy than in normal rats. Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling with increased expression of ventricular atrial natriuretic factor and interstitial collagen deposition and died prematurely of heart failure. Neither the systolic blood pressure nor the heart rate were changed [125]. AT1R overexpression in the mouse myocardium produces a lethal phenotype associated with myocyte hyperplasia and heart block [56]. Increased expression of cardiac AT1a receptors decreases myocardial microvessel density after experimental myocardial infarction and this is amenable to AT(1) receptor blockade, suggesting that efficacy of AT1 receptor blockers post-myocardial infarction may be due to a stimulatory effect on angiogenesis [33]. Overexpression of AT1a receptors impairs excitation-contraction coupling in the mouse heart before the development of cardiac hypertrophy [134]. Overexpression of AT(1) receptor under the control of alpha-myosin heavy chain promoter in angiotensinogen-knockout background mice showed spontaneous systolic dysfunction and chamber dilatation, accompanied by severe interstitial fibrosis. Progression of cardiac remodeling in this model was prevented by treatment with candesartan, an inverse agonist for the AT(1) receptor demonstrating that constitutive activity of the AT(1) receptor under basal conditions contributes to the cardiac remodeling even in the absence of Ang II, when the AT(1) receptor is upregulated in the heart [174]. Transgenic rat model that exhibits an upregulated myocardial AT1 receptor density demonstrates augmented cardiac hypertrophy and contractile response to angiotensin II after volume and pressure overload, but not under baseline conditions [60]. Brain-selective overexpression of AT1a receptors resulted in enhanced cardiovascular responsiveness to intracerebroventricular (ICV) Ang II injection with no change in baseline blood. However, blockade of central AT1 receptors with ICV losartan reduced basal blood pressure suggesting an enhanced contribution of central AT1 receptors to the maintenance of baseline blood pressure in this model [88]. Renovascular hypertension in mice with brain-selective overexpression of AT1a receptors is buffered by increased nitric oxide production in the periphery suggesting that activation of endogenous NO systems plays an important role in buffering the maintenance of hypertension caused by overexpression of AT(1a) receptors in the brain [89]. Brain-selective overexpression of AT(1A) receptors results in enhanced salt appetite and altered water intake [90]. AT1 receptor overexpression in podocytes induces protein leakage and structural podocyte damage progressing to focal segmental glomerulosclerosis in transgenic rats [61]. Mice with overexpression of a constitutively active AT1a receptor transgene in renal proximal tubule caused increased baseline blood pressure. Depletion of endogenous AT1a receptors in the proximal tubule reduced blood pressure. In contrast to the changes observed at baseline, there was no difference in the blood pressure response to a pressor dose of Ang II in either experimental model suggesting that Ang II signaling via the AT1a receptor in the renal proximal tubule is a regulator of systemic blood pressure under baseline conditions [93]. | ||||||||||
| Phenotypes, Alleles and Disease Models
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| Clinically-Relevant Mutations and Pathophysiology
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| Clinically-Relevant Mutations and Pathophysiology Comments | ||||||||||||
| Other pathophysiological actions of AT1 receptor include induction of cardiac fibrosis, renal fibrosis, perivascular fibrosis, induction of cell and tissue senescence, induction of insulin resistance, induction of endothelial dysfunction, induction of skeletal muscle wasting, reduction of exercise tolerance, induction of tissue ER stress, induction of aortic aneurysm, acceleration of atherosclerosis. Preeclampsia is associated with the presence of autoantibodies capable of activating the AT1R [164,169]. AT(1)-B(2)-receptor heterodimerization is also reported to be correlated to preeclampsia [1]. | ||||||||||||
| Biologically Significant Variants
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| General Comments |
| For information on miRNAs predicted to target AGTR1 3'-UTR please see TargetScan [47,92]. |
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