Affinage

AGTR1

Type-1 angiotensin II receptor · UniProt P30556

Round 2 corrected
Length
359 aa
Mass
41.1 kDa
Annotated
2026-04-28
130 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AGTR1 encodes the angiotensin II type 1 receptor (AT1R), a G protein-coupled receptor that transduces angiotensin II signals through multiple parallel pathways—Gq/11-mediated phospholipase C/IP3/Ca²⁺/PKC activation, Gi/o and G12/13 coupling, direct recruitment and activation of Jak2/Tyk2 kinases signaling to STAT1/STAT2, and G protein-independent β-arrestin-2 scaffolding of cRaf-1–MEK1–ERK2 complexes on endosomes that restricts ERK to the cytosol (PMID:7746328, PMID:11226259, PMID:16141358). Agonist-stimulated GRK2/3/5 phosphorylation of C-terminal serine/threonine clusters drives stable β-arrestin-2 association, clathrin/dynamin-dependent internalization, and homologous desensitization, while receptor surface density is further controlled by CD74-mediated ER retention, SNX1-directed proteasomal degradation, miR-155-dependent allele-specific mRNA silencing, and translational regulation via 5′-leader RNA-binding proteins (PMID:8662816, PMID:11279203, PMID:18719072, PMID:33972750, PMID:17668390, PMID:12810582). Crystal structures reveal an intramembrane ligand-binding pocket and a polar sodium-coordination network that functions as a biased-signaling switch distinguishing balanced from β-arrestin-biased agonist conformations (PMID:25913193, PMID:32079768). Loss-of-function mutations in AGTR1 cause autosomal recessive renal tubular dysgenesis, establishing an essential role for AT1R signaling in fetal proximal tubule development (PMID:16116425).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 High

    Discovery that AT1R directly recruits and activates Jak2 and Tyk2 established that a GPCR can co-opt JAK/STAT signaling previously thought exclusive to cytokine receptors, broadening the signaling repertoire of AT1R beyond canonical G protein pathways.

    Evidence Co-immunoprecipitation and in vitro kinase assays in rat aortic smooth-muscle cells

    PMID:7746328

    Open questions at the time
    • Structural basis of Jak2 binding to AT1R is undefined
    • Whether JAK/STAT signaling occurs from the plasma membrane or endosomes is unresolved
  2. 1996 High

    Identification of GRK2/3/5 and PKC as AT1R kinases, with only GRK-mediated phosphorylation required for homologous desensitization, separated heterologous from homologous desensitization mechanisms and set the stage for understanding β-arrestin recruitment specificity.

    Evidence ³²P metabolic labeling, dominant-negative GRK2, PKC inhibitor, and GTPase activity assay

    PMID:8662816

    Open questions at the time
    • Individual phosphosite contributions were not resolved at this stage
    • Relative contributions of GRK5 vs GRK2/3 in vivo remain unclear
  3. 2000 High

    Demonstration of stable AT1R–bradykinin B2 receptor heterodimers with enhanced Gq/Gi signaling revealed that AT1R function is context-dependent through GPCR heterodimerization, explaining tissue-specific AngII sensitivity.

    Evidence Co-IP, FRET, IP3/cAMP assays in transfected cells and human myometrial biopsies

    PMID:10993080

    Open questions at the time
    • Stoichiometry and structural interface of the heterodimer are unknown
    • Whether heterodimerization is regulated dynamically in vivo needs clarification
  4. 2001 High

    A series of studies collectively established the β-arrestin-2 signaling paradigm at AT1R: C-tail serine/threonine clusters mediate stable β-arrestin-2 binding, which scaffolds cRaf-1–MEK1–ERK2 on endosomes, sequestering active ERK in the cytosol rather than the nucleus—defining a G protein-independent, non-mitogenic MAPK signaling mode and a clathrin/dynamin-dependent internalization mechanism.

    Evidence Live-cell imaging with β-arrestin-2-GFP, C-tail mutagenesis, chimeric receptor swaps, subcellular fractionation, dominant-negative dynamin/β-arrestin mutants across HEK293/COS-7/CHO cells

    PMID:11160859 PMID:11226259 PMID:11279203 PMID:12473660

    Open questions at the time
    • Phosphosite-specific codes for biased β-arrestin conformations remain incomplete
    • In vivo validation of endosomal ERK signaling from AT1R is limited
  5. 2001 High

    AT2R was shown to directly bind and antagonize AT1R independently of AT2R's own signaling, establishing ligand-independent receptor–receptor antagonism as a regulatory mechanism for AT1R output.

    Evidence Co-IP and functional antagonism assays in cell lines and human myometrial biopsies

    PMID:11507095

    Open questions at the time
    • Interface residues mediating AT1R–AT2R interaction are unmapped
    • Physiological ratio requirements for antagonism in different tissues are uncharacterized
  6. 2003 High

    Estrogen was found to suppress AT1R protein without changing mRNA levels by recruiting RNA-binding proteins to the 5′ leader sequence that shift AT1R mRNA off polysomes, revealing a translational control layer governing receptor density.

    Evidence Polysome fractionation, RNA gel-shift with 5′LS, in vivo aldosterone assay in ovariectomized rats

    PMID:12810582

    Open questions at the time
    • Identity of the specific RNA-binding proteins involved is unknown
    • Whether this translational mechanism operates in non-adrenal tissues is untested
  7. 2005 High

    Human genetic studies identified homozygous and compound heterozygous AGTR1 loss-of-function mutations as causative for autosomal recessive renal tubular dysgenesis, proving AT1R is essential for fetal kidney development in humans.

    Evidence Homozygosity mapping and sequencing in 11 individuals from 9 families

    PMID:16116425

    Open questions at the time
    • Downstream developmental signaling pathways in proximal tubule formation are undefined
    • Whether partial loss-of-function alleles cause milder phenotypes is unexplored
  8. 2007 High

    The discovery that miR-155 silences AGTR1 only from the A allele at rs5186, not the C allele, provided a molecular mechanism for the cardiovascular risk association of the 1166C variant and linked non-coding variation to receptor expression levels.

    Evidence Luciferase reporter assay with allele-specific constructs and Western blot in trisomy 21-discordant twin fibroblasts

    PMID:17668390

    Open questions at the time
    • Quantitative contribution of miR-155 to AT1R levels in cardiovascular tissues in vivo is undetermined
    • Other miRNAs targeting AGTR1 3′UTR may exist
  9. 2008 High

    CD74 was identified as a direct AT1R-binding partner that retains the receptor in the ER and promotes its proteasomal degradation, establishing a quality-control checkpoint for AT1R surface expression.

    Evidence Yeast two-hybrid, co-IP, confocal co-localization, proteasome inhibitor rescue in CHO-K1 cells

    PMID:18719072

    Open questions at the time
    • Whether CD74-mediated retention is dynamically regulated by immune signals is unknown
    • Ubiquitination site(s) involved in CD74-directed degradation are not mapped
  10. 2015 High

    The first crystal structure of human AT1R (2.9 Å with antagonist ZD7155) defined the intramembrane binding pocket architecture and enabled docking of clinically used ARBs, providing a structural template for understanding receptor pharmacology.

    Evidence Serial femtosecond crystallography at an X-ray free-electron laser

    PMID:25913193

    Open questions at the time
    • No structure of the receptor in complex with G protein or β-arrestin was available at this time
    • Allosteric modulator binding sites were not resolved
  11. 2018 High

    AT1R–B2R heteromer formation was causally linked to preeclampsia in vivo: increased heteromerization drove exaggerated calcium signaling and mechanosensitivity in pregnant mice, while transgenic β-arrestin-1 expression prevented symptoms by promoting heteromer downregulation.

    Evidence BRET/FRET, transgenic mouse models, calcium signaling, blood pressure measurements, human placental biopsy co-IP

    PMID:30503206

    Open questions at the time
    • Therapeutic disruption of the heteromer without blocking monomeric AT1R or B2R function is unexplored
    • Whether heteromer levels predict preeclampsia risk in humans requires clinical validation
  12. 2020 High

    Crystal structures of AT1R bound to AngII and two β-arrestin-biased analogs revealed that a polar sodium-binding network acts as a conformational switch: balanced agonists induce large rearrangements across this network while biased ligands stabilize a distinct conformation selectively activating β-arrestin, providing a structural basis for biased agonism.

    Evidence X-ray crystallography (2.7–2.9 Å) with three ligands plus molecular dynamics simulations

    PMID:32079768

    Open questions at the time
    • How conformational differences propagate to the intracellular face to discriminate Gq from β-arrestin engagement remains structurally unresolved
    • No cryo-EM structure of a ternary AT1R–β-arrestin complex exists
  13. 2021 High

    SNX1 was shown to direct AT1R ubiquitination and proteasomal (not lysosomal) degradation; SNX1 knockout increased AT1R stability and expression, causing enhanced vasoconstriction and hypertension, establishing a post-endocytic sorting mechanism that controls receptor abundance in vivo.

    Evidence CRISPR SNX1-knockout mice, co-IP, cycloheximide chase, proteasome vs. lysosome inhibitors, ubiquitination assays

    PMID:33972750

    Open questions at the time
    • The E3 ubiquitin ligase recruited by SNX1 for AT1R ubiquitination is unidentified
    • Whether SNX1-mediated sorting is specific to AT1R or applies to other GPCRs is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key outstanding questions include the structural basis of ternary AT1R–transducer complexes (AT1R–Gq, AT1R–β-arrestin), the identity of the RNA-binding proteins mediating translational control via the 5′ leader, and how AT1R heterodimer stoichiometry is regulated across tissues to produce context-specific signaling outputs.
  • No cryo-EM or crystal structure of AT1R in complex with Gq or β-arrestin
  • 5′ leader RNA-binding protein identities remain unknown
  • Tissue-specific heterodimer regulation mechanisms are uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 3 GO:0031410 cytoplasmic vesicle 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-392499 Metabolism of proteins 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-1266738 Developmental Biology 1 R-HSA-168256 Immune System 1
Partners
AGTR2ARRB2BDKRB2CD74GRK2GRK5JAK2SNX1
Complex memberships
AT1R–AT2R heterodimerAT1R–B2R heterodimer

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 The AT1 receptor directly stimulates the JAK/STAT pathway: angiotensin II induces rapid tyrosine phosphorylation and activation of Jak2 and Tyk2 in rat aortic smooth-muscle cells, and Jak2 co-precipitates with the AT1 receptor, indicating that this GPCR can signal through intracellular phosphorylation pathways used by cytokine receptors. Co-immunoprecipitation, in vitro kinase assay, Western blot for tyrosine phosphorylation of STAT1/STAT2 Nature High 7746328
1996 The AT1A receptor is phosphorylated by GRK2, GRK3, and GRK5 as well as protein kinase C (PKC) upon agonist stimulation; GRK-mediated phosphorylation (but not PKC-mediated phosphorylation) is required for homologous desensitization of the receptor. 32Pi metabolic labeling, immunoprecipitation of receptor, dominant-negative GRK2 overexpression, PKC inhibitor (staurosporine), GTPase activity assay The Journal of biological chemistry High 8662816
2000 AT1 receptor forms stable heterodimers with the bradykinin B2 receptor, causing enhanced activation of Gαq and Gαi proteins and altered endocytotic trafficking of both receptors. Co-immunoprecipitation, FRET, G-protein activation assays (IP3 production, cAMP), receptor internalization assays in transfected cells and human myometrial biopsies Nature High 10993080
2001 Beta-arrestin-2 scaffolds AT1aR with cRaf-1, MEK1, and ERK2 into endosomal complexes upon angiotensin II stimulation, targeting activated ERK2 to endosomal vesicles rather than the nucleus. Confocal immunofluorescence microscopy, co-immunoprecipitation, RFP-tagged ERK2 redistribution imaging, dominant-negative constructs Proceedings of the National Academy of Sciences of the United States of America High 11226259
2001 AT1 receptor (AT1A subtype) undergoes agonist-induced internalization via clathrin-coated vesicles in a beta-arrestin- and dynamin-dependent manner at physiological angiotensin II concentrations; dominant-negative forms of beta-arrestin1 and dynamin-1/2 block this endocytosis. Hyperosmotic sucrose treatment (clathrin depletion), filipin treatment (caveolae inhibition), dominant-negative beta-arrestin1 and dynamin mutants, radioligand internalization assay, confocal microscopy with fluorescein-AngII and transferrin co-localization Molecular pharmacology High 11160859
2001 The AT2 receptor binds directly to the AT1 receptor and antagonizes AT1 receptor function in a manner independent of AT2 receptor activation or signaling; this constitutes a receptor-specific antagonism via direct GPCR-GPCR interaction. Co-immunoprecipitation, functional signaling assays in multiple cell types and human myometrial biopsies, AT2 receptor-specific antagonist controls The Journal of biological chemistry High 11507095
2001 Angiotensin II stimulation of AT1 receptor inhibits preadipocyte differentiation via Ang II type 1 receptors; AT1 receptor blockade markedly enhances adipogenesis in primary human preadipocytes, and mature adipocytes inhibit preadipocyte differentiation through a paracrine AT1 receptor-dependent mechanism. Primary human preadipocyte culture, co-culture experiments with mature adipocytes, Ang II receptor antagonist treatment, quantitative gene expression (RAS components during adipogenesis) Diabetes Medium 12031955
2001 The stability of the AT1aR–beta-arrestin complex determines the mechanism and functional consequence of ERK activation: stable complexes (as formed by AT1aR) generate cytosolic beta-arrestin-bound ERK that is excluded from the nucleus and thus non-mitogenic, in contrast to transient complexes that allow nuclear ERK and mitogenesis. COS-7 transfection with chimeric receptors (AT1aR/V2 C-tail swaps), beta-arrestin-2-GFP co-precipitation, cell fractionation for nuclear vs. cytosolic phospho-ERK, Elk-1 luciferase reporter, mitogenesis assay The Journal of biological chemistry High 12473660
2001 Specific serine/threonine clusters in the AT1A receptor C-terminal tail mediate stable beta-arrestin-2 binding and co-internalization into endocytic vesicles; receptor mutagenesis of these clusters abolishes stable beta-arrestin association. Live-cell imaging with beta-arrestin-2-GFP, receptor C-tail mutagenesis, co-internalization assay in HEK-293 cells The Journal of biological chemistry High 11279203
2004 AT1 receptor heterodimer formation with bradykinin B2 receptor is associated with increased angiotensin II sensitivity in preeclampsia; AT1-B2 heterodimers are found in platelets and omental vessels of preeclamptic women and display enhanced signaling. Co-immunoprecipitation from human platelets and omental vessel biopsies, functional AngII responsiveness assay, AT1-specific and B2-specific receptor antagonist controls Seminars in nephrology Medium 15017523
2005 Angiotensin II AT1 receptor activates a broad spectrum of signaling pathways via Gq/11 (stimulating phospholipases A2, C, and D, IP3/Ca2+, PKC isoforms, MAPKs), Gi/o, G12/13, several tyrosine kinases (Pyk2, Src, Tyk2, FAK), and scaffold proteins; it also signals via G protein-independent pathways including beta-arrestin-mediated MAPK activation and the JAK/STAT pathway. Review integrating results from multiple experimental studies (signaling assays, dominant-negatives, kinase assays) Molecular endocrinology (Baltimore, Md.) High 16141358
2007 The A1166C SNP (rs5186) in the 3'-UTR of the AGTR1 gene disrupts the binding site for miR-155; miR-155 down-regulates AGTR1 expression only from the 1166A allele and not the 1166C allele, and trisomy 21 (with an extra copy of miR-155 on chromosome 21) leads to reduced AGTR1 protein levels in fibroblasts. Luciferase reporter silencing assay with miR-155 and 1166A vs. 1166C allele constructs, Western blot of AGTR1 protein in monozygotic twins discordant for trisomy 21 American journal of human genetics High 17668390
2008 CD74 (invariant chain) binds to the membrane-proximal region of the AT1 receptor cytoplasmic C-terminal tail, retains the receptor in the endoplasmic reticulum, promotes its proteasomal degradation, and reduces AT1 receptor surface density. Yeast two-hybrid screen (human kidney cDNA library), co-immunoprecipitation, co-localization (confocal microscopy), surface expression assay (radioligand binding), proteasome inhibitor treatment in CHO-K1 cells The Journal of endocrinology High 18719072
2009 AGTR1 overexpression in primary mammary epithelial cells, combined with angiotensin II stimulation, leads to a highly invasive phenotype that is attenuated by the AT1 receptor antagonist losartan; losartan also reduces tumor growth in AGTR1-positive breast cancer xenografts. Ectopic AGTR1 overexpression in primary mammary epithelial cells, invasion assay, xenograft tumor growth assay with losartan treatment Proceedings of the National Academy of Sciences of the United States of America Medium 19487683
2013 GRK4γ variant 142V directly interacts with AT1 receptor and decreases AT1R phosphorylation, leading to reduced AT1R degradation and increased AT1R protein expression via NF-κB-dependent transcriptional upregulation; this results in enhanced AngII-mediated vasoconstriction. Co-immunoprecipitation (GRK4γ–AT1R interaction), NF-κB reporter assay, ChIP (NF-κB binding to AT1R promoter), cycloheximide chase assay (protein stability), immunofluorescence in A10 cells and GRK4γ 142V transgenic mice, vascular contractility assay Hypertension (Dallas, Tex. : 1979) High 24218433
2013 2-Methoxyestradiol (2ME2) downregulates AT1 receptor expression through GPR30 located on endoplasmic reticulum membranes; GPR30 activation leads to EGFR transactivation and ERK1/2 phosphorylation as the required signaling step for AT1R downregulation. Specific [3H]2ME2 radioligand binding assays with GPR30 agonist (G1)/antagonist (G15) competition, cell fractionation (ER localization of GPR30), GPR30 antagonist rescue of AT1R expression, ERK1/2 phosphorylation assays, EGF treatment European journal of pharmacology Medium 24262995
2015 Crystal structure of the human AT1R in complex with antagonist ZD7155 at 2.9 Å resolution (determined by serial femtosecond crystallography) reveals the structural basis for ligand binding; docking simulations with clinically used ARBs (losartan, candesartan, etc.) identify both common and distinct binding modes within the intramembrane binding pocket. Serial femtosecond crystallography at X-ray free-electron laser, 2.9-Å crystal structure, docking simulations of ARBs Cell High 25913193
2015 Position 4 of angiotensin II confers bias toward ERK signaling over Gq signaling, while position 8 confers bias toward β-arrestin recruitment over ERK and Gq signaling; position 8 analogs act as partial agonists of a PKC-dependent ERK pathway through atypical PKCζ and PKCι isoforms. Six parallel signaling assays (Gq, G12, ERK via Gq/PKC, ERK via PKCζ/ι, ERK via beta-arrestin, beta-arrestin recruitment) in HEK293 cells with systematic AngII peptide analog series (modifications at positions 1, 4, and 8) Molecular pharmacology High 25808928
2018 AT1 receptor forms heteromers with the bradykinin B2 receptor; increased AT1-B2 heteromer formation triggers exaggerated calcium signaling and high vascular smooth muscle mechanosensitivity that causes preeclampsia symptoms in pregnant mice; beta-arrestin-mediated downregulation inhibits AT1-B2 heteromer formation, and transgenic ARRB1 expression prevents preeclampsia symptoms. BRET and FRET (heteromerization in transfected cells and transgenic mice), transgenic mouse models (AT1-B2 heteromer-overexpressing and ARRB1-transgenic mice), calcium signaling assays, blood pressure measurements, human placental biopsy co-immunoprecipitation Cell High 30503206
2020 Crystal structures of AT1R (2.7–2.9 Å) bound to the balanced agonist AngII and two β-arrestin-biased analogs reveal distinct active conformations: AngII promotes larger rearrangements in the ligand-binding pocket and in a key polar network (a sodium-binding site in most GPCRs) that acts as a biased signaling switch; β-arrestin-biased ligands stabilize a conformation capable of activating β-arrestin but not Gq. X-ray crystallography (2.7–2.9 Å structures of AT1R with three ligands), molecular dynamics simulations, comparative structural analysis Science (New York, N.Y.) High 32079768
2005 Mutations in the AGTR1 gene (encoding AT1 receptor) cause autosomal recessive renal tubular dysgenesis, establishing an essential in vivo role for AT1 receptor signaling in fetal proximal tubule development and renal perfusion. Genetic analysis (homozygosity mapping, sequencing) of AGTR1 and other RAS genes in 11 individuals from 9 families with renal tubular dysgenesis; identification of homozygous/compound heterozygous loss-of-function mutations Nature genetics High 16116425
2021 Sorting nexin 1 (SNX1) directly interacts with AT1R in aortic vascular smooth muscle cells, sorts AT1R for proteasomal (not lysosomal) degradation, and its absence leads to decreased ubiquitination and increased AT1R protein stability, resulting in elevated AT1R expression, enhanced AngII-mediated vasoconstriction, and hypertension. SNX1-/- mice (CRISPR/Cas9), co-immunoprecipitation, immunofluorescence co-localization, SNX1 siRNA knockdown in A10 cells, cycloheximide chase assay (protein stability), proteasome vs. lysosome inhibitor treatment, ubiquitin-AT1R binding assay, confocal microscopy with PSMD6 (proteasomal marker) Hypertension research : official journal of the Japanese Society of Hypertension High 33972750
2003 Estrogen reduces AT1 receptor density in the adrenal cortex primarily by inhibiting AT1R mRNA translation (without changing mRNA levels), mediated through RNA-binding proteins that bind the 5' leader sequence and shift the AT1R mRNA polysome distribution to lighter fractions, reducing AngII-induced aldosterone release. Sucrose gradient polysome fractionation of AT1R mRNA, RNA-binding protein (RBP) gel-shift assays with 5'LS, coding region, and 3'UTR of AT1R mRNA, radioligand binding (AT1R density), in vivo aldosterone secretion assay in ovariectomized rats ± estrogen Endocrinology High 12810582
2012 Nitric oxide (NO) inhibits AT1 receptor expression in neurons via a cGMP/PKG-dependent signaling pathway; nNOS antisense knockdown increases AT1R expression and augments AngII-induced intracellular Ca2+ rise, while nNOS overexpression (adenoviral) suppresses AT1R expression and blunts AngII-stimulated Ca2+ signaling. NO donor (SNP) and NOS inhibitor (l-NMMA) dose-response in primary hypothalamic neuronal culture, antisense nNOS transfection, adenoviral nNOS overexpression, PKG inhibitor and peroxynitrite scavenger controls, mRNA and protein quantification, intracellular Ca2+ assay American journal of physiology. Cell physiology Medium 22218225
2014 Tudor-SN (human Tudor staphylococcal nuclease) binds to the 3'UTR of AGTR1 mRNA and co-localizes with it in stress granules; Tudor-SN knockdown decreases the recovery kinetics of AGTR1-3'UTR granule formation, indicating a role in AT1R mRNA stress-granule dynamics. RNA immunoprecipitation (RIP), RNA pull-down, luciferase reporter with AGTR1-3'UTR, co-localization (confocal microscopy), Tudor-SN siRNA knockdown with granule recovery kinetics assay FEBS letters Medium 24815690
2017 miR-34a-5p promotes multi-chemoresistance in osteosarcoma by repressing AGTR1 expression; AGTR1 downregulation suppresses apoptosis in drug-sensitive OS cells, while AGTR1 overexpression sensitizes resistant cells to drug-induced cell death, establishing AGTR1 as a positive regulator of chemotherapy-induced apoptosis in OS. miR-34a-5p mimic/antagomiR transfection, siRNA-mediated AGTR1 knockdown, AGTR1 overexpression, apoptosis assay, cell viability in multi-drug-sensitive (G-292) and -resistant (SJSA-1) OS cell lines BMC cancer Medium 28073349

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2002 Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. The Journal of clinical investigation 1101 12045255
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2018 Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiological reviews 852 29873596
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2001 Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proceedings of the National Academy of Sciences of the United States of America 685 11226259
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1995 Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature 653 7746328
1994 Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension (Dallas, Tex. : 1979) 634 8021009
2005 Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. Molecular endocrinology (Baltimore, Md.) 425 16141358
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2000 AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration. Nature 393 10993080
2001 Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-beta-arrestin complexes after receptor endocytosis*. The Journal of biological chemistry 377 11279203
2001 The angiotensin II AT2 receptor is an AT1 receptor antagonist. The Journal of biological chemistry 361 11507095
2003 Angiotensin AT1/AT2 receptors: regulation, signalling and function. Blood pressure 353 12797627
1999 Statin-sensitive dysregulated AT1 receptor function and density in hypercholesterolemic men. Circulation 332 10571970
2007 Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3' untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes. American journal of human genetics 302 17668390
2015 Structure of the Angiotensin receptor revealed by serial femtosecond crystallography. Cell 301 25913193
2001 Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver. Proceedings of the National Academy of Sciences of the United States of America 300 11752456
2005 Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circulation research 296 15718497
2002 The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation. The Journal of biological chemistry 293 12473660
2002 Mature adipocytes inhibit in vitro differentiation of human preadipocytes via angiotensin type 1 receptors. Diabetes 269 12031955
2000 Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. Journal of human hypertension 245 10854085
2011 Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors. Clinical science (London, England : 1979) 243 21542804
2009 Devil and angel in the renin-angiotensin system: ACE-angiotensin II-AT1 receptor axis vs. ACE2-angiotensin-(1-7)-Mas receptor axis. Hypertension research : official journal of the Japanese Society of Hypertension 243 19461648
2021 Soluble ACE2-mediated cell entry of SARS-CoV-2 via interaction with proteins related to the renin-angiotensin system. Cell 227 33713620
1999 Distribution of angiotensin AT1 and AT2 receptor subtypes in the rat kidney. The American journal of physiology 223 10484527
2010 Poor replication of candidate genes for major depressive disorder using genome-wide association data. Molecular psychiatry 220 20351714
1996 Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled receptor kinases and protein kinase C. The Journal of biological chemistry 213 8662816
2006 Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox. Circulation 208 16923768
1998 Angiotensin receptors in the nervous system. Brain research bulletin 195 9766385
2000 Localization and function of angiotensin AT1 receptors. American journal of hypertension 193 10678286
2020 Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR. Science (New York, N.Y.) 192 32079768
2001 Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide. American journal of physiology. Heart and circulatory physiology 192 11709400
2005 Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nature genetics 182 16116425
2017 AT1 receptor signaling pathways in the cardiovascular system. Pharmacological research 180 28527699
2009 AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist. Proceedings of the National Academy of Sciences of the United States of America 138 19487683
1997 Hypercholesterolemia is associated with enhanced angiotensin AT1-receptor expression. The American journal of physiology 115 9227549
2008 AT1-receptor blockade by telmisartan upregulates GTP-cyclohydrolase I and protects eNOS in diabetic rats. Free radical biology & medicine 109 18539157
2003 Postovariectomy hypertension is linked to increased renal AT1 receptor and salt sensitivity. Hypertension (Dallas, Tex. : 1979) 100 14610098
1996 The ligand binding site of the angiotensin AT1 receptor. Trends in pharmacological sciences 97 8984739
2005 Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat. Regulatory peptides 95 15544836
2001 Beta-arrestin- and dynamin-dependent endocytosis of the AT1 angiotensin receptor. Molecular pharmacology 95 11160859
2006 Pathophysiological regulation of the AT1-receptor and implications for vascular disease. Journal of hypertension. Supplement : official journal of the International Society of Hypertension 93 16601568
2000 Mechanisms and functions of AT(1) angiotensin receptor internalization. Regulatory peptides 93 10967200
2002 Angiotensin AT1 receptor signalling pathways in neurons. Clinical and experimental pharmacology & physiology 84 12010196
1997 Losartan, an orally active angiotensin (AT1) receptor antagonist: a review of its efficacy and safety in essential hypertension. Pharmacology & therapeutics 83 9336021
2008 Sartan-AT1 receptor interactions: in vitro evidence for insurmountable antagonism and inverse agonism. Molecular and cellular endocrinology 82 18620019
2003 Perturbation of D1 dopamine and AT1 receptor interaction in spontaneously hypertensive rats. Hypertension (Dallas, Tex. : 1979) 81 12900438
1999 Regulation of angiotensin II type 1 (AT1) receptor function. Regulatory peptides 81 9930579
2003 Estrogen regulates adrenal angiotensin AT1 receptors by modulating AT1 receptor translation. Endocrinology 78 12810582
1998 Physiological and pharmacological implications of AT1 versus AT2 receptors. Kidney international. Supplement 78 9736262
2004 Cancer, inflammation and the AT1 and AT2 receptors. Journal of inflammation (London, England) 77 15813980
2023 p53 governs an AT1 differentiation programme in lung cancer suppression. Nature 70 37468633
2000 Angiotensin AT1 receptor over-expression in hypercholesterolaemia. Annals of medicine 68 11028685
2010 Angiotensin II receptor type 1 (AT1) selective nonpeptidic antagonists--a perspective. Bioorganic & medicinal chemistry 60 21071232
2006 Agonistic antibodies directed at the angiotensin II, AT1 receptor in preeclampsia. Journal of the Society for Gynecologic Investigation 60 16443499
2000 Interaction between Mas and the angiotensin AT1 receptor in the amygdala. Journal of neurophysiology 60 10758111
2006 Intracellular angiotensin II induces cell proliferation independent of AT1 receptor. American journal of physiology. Cell physiology 59 16774988
2017 The miR-34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene. BMC cancer 58 28073349
2008 Blockade of AT1 receptor improves adipocyte differentiation in atherosclerotic and diabetic models. American journal of hypertension 58 18188158
1999 Localization of angiotensin AT1 and AT2 receptors. Journal of the American Society of Nephrology : JASN 58 9892137
2008 Autoantibody against AT1 receptor from preeclamptic patients induces vasoconstriction through angiotensin receptor activation. Journal of hypertension 55 18622242
2018 Beta-Arrestin1 Prevents Preeclampsia by Downregulation of Mechanosensitive AT1-B2 Receptor Heteromers. Cell 53 30503206
2002 Effect of estrogen and AT1 receptor blocker on neointima formation. Hypertension (Dallas, Tex. : 1979) 53 12364346
2012 SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B are markers of resistance to neoadjuvant chemotherapy in HER2-negative breast cancer. Breast cancer research and treatment 52 23203637
2022 Polymorphisms in ACE, ACE2, AGTR1 genes and severity of COVID-19 disease. PloS one 50 35120165
2003 Losartan's molecular basis of interaction with membranes and AT1 receptor. Chemistry and physics of lipids 50 14625072
1997 Somatic mutations of the angiotensin II (AT1) receptor gene are not present in aldosterone-producing adenoma. The Journal of clinical endocrinology and metabolism 50 9024263
2000 Renal responses to AT1 receptor blockade. American journal of hypertension 47 10678288
2010 Endothelium-derived vasoactive agents, AT1 receptors and inflammation. Pharmacology & therapeutics 45 21115037
2014 Autoimmune mechanisms activating the angiotensin AT1 receptor in 'primary' aldosteronism. The Journal of clinical endocrinology and metabolism 43 24552217
2004 Multiple Polymorphisms in the renin- angiotensin-aldosterone system (ACE, CYP11B2, AGTR1) and their contribution to hypertension in African Americans and Latinos in the multiethnic cohort. The American journal of the medical sciences 43 15545843
1999 Role of angiotensin AT1, and AT2 receptors in cardiac hypertrophy and disease. The American journal of cardiology 42 10750587
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2013 2-methoxyestradiol binding of GPR30 down-regulates angiotensin AT(1) receptor. European journal of pharmacology 41 24262995
2005 Activating auto-antibodies against the AT1 receptor in preeclampsia. Autoimmunity reviews 41 15652781
2004 AT1 receptor heterodimers and angiotensin II responsiveness in preeclampsia. Seminars in nephrology 41 15017523
2004 Exploring type I angiotensin (AT1) receptor functions through gene targeting. Acta physiologica Scandinavica 40 15283771
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2011 A polymorphic miR-155 binding site in AGTR1 is associated with cardiac hypertrophy in Friedreich ataxia. Journal of molecular and cellular cardiology 33 21771600
2016 Protective Effect of Irbesartan an Angiotensin (AT1) Receptor Antagonist in Unpredictable Chronic Mild Stress Induced Depression in Mice. Drug research 32 27756096
2012 Nitric oxide inhibits the expression of AT1 receptors in neurons. American journal of physiology. Cell physiology 31 22218225
2008 Effects of AGTR1 A1166C gene polymorphism in patients with heart failure treated with candesartan. The Annals of pharmacotherapy 31 18594050
2014 Dual targeting of angiotensin receptors (AGTR1 and AGTR2) in epithelial ovarian carcinoma. Gynecologic oncology 29 25014541
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2006 Translocation of AT1- and AT2-receptors by higher concentrations of angiotensin II in the smooth muscle cells of rat internal anal sphincter. The Journal of pharmacology and experimental therapeutics 27 16985169
2001 Angiotensin II type 1 (AT1) receptor antagonists in the treatment of hypertension after renal transplantation. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 27 11369838
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1997 Regulation of the angiotensin AT1 receptor expression by hypercholesterolemia. European journal of medical research 27 9233901
2013 Insights into AT1 receptor activation through AngII binding studies. Journal of chemical information and modeling 26 24053563
2010 ACE and AGTR1 polymorphisms and left ventricular hypertrophy in endurance athletes. Medicine and science in sports and exercise 26 19997001
2015 Characterization of Angiotensin II Molecular Determinants Involved in AT1 Receptor Functional Selectivity. Molecular pharmacology 25 25808928
2009 Effects of AT1- and beta-adrenergic receptor antagonists on TGF-beta1-induced fibrosis in transgenic mice. European journal of clinical investigation 25 19522835
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1998 Role of ACE inhibition or AT1 blockade in the remodeling following myocardial infarction. Basic research in cardiology 24 9833170
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1994 Genetic polymorphisms of the angiotensin II type 1 (AT1) receptor gene. European heart journal 23 7713099
2021 LINC00852 promotes the proliferation and invasion of ovarian cancer cells by competitively binding with miR-140-3p to regulate AGTR1 expression. BMC cancer 22 34496800
2018 Qiliqiangxin Rescues Mouse Cardiac Function by Regulating AGTR1/TRPV1-Mediated Autophagy in STZ-Induced Diabetes Mellitus. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 22 29929188
2007 Synergism between AT1 receptor and hyperhomocysteinemia during vascular remodeling. Clinical chemistry and laboratory medicine 22 17990952
2015 PPARG, AGTR1, CXCL16 and LGALS2 polymorphisms are correlated with the risk for coronary heart disease. International journal of clinical and experimental pathology 21 26045830
2015 Erythropoiesis and Blood Pressure Are Regulated via AT1 Receptor by Distinctive Pathways. PloS one 21 26107632
2014 Vasopressor meets vasodepressor: The AT1-B2 receptor heterodimer. Biochemical pharmacology 21 24462918
2014 A polymorphism in AGT and AGTR1 gene is associated with lead-related high blood pressure. Journal of the renin-angiotensin-aldosterone system : JRAAS 21 25031294
2010 Early inflammatory and metabolic changes in association with AGTR1 polymorphisms in prehypertensive subjects. American journal of hypertension 21 20864943
2009 Expression of angiotensin II type 1 (AT1) and angiotensin II type 2 (AT2) receptors in human granulosa-lutein (GL) cells: correlation with infertility diagnoses. Fertility and sterility 21 19524223
2017 AGTR1 promoter hypermethylation in lung squamous cell carcinoma but not in lung adenocarcinoma. Oncology letters 20 29085512
2006 Increased expression of angiotensin II type 1 receptor (AGTR1) in heart transplant recipients with recurrent rejection. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20 17097490
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2014 Human Tudor staphylococcal nuclease (Tudor-SN) protein modulates the kinetics of AGTR1-3'UTR granule formation. FEBS letters 19 24815690
2012 Association of maternal AGTR1 polymorphisms and preeclampsia: a systematic review and meta-analysis. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 18 22758920
2011 Effects of captopril and angiotensin II receptor blockers (AT1, AT2) on myocardial ischemia-reperfusion induced infarct size. Cytokine 18 21975128
2022 Downregulation of ACE, AGTR1, and ACE2 genes mediating SARS-CoV-2 pathogenesis by gut microbiota members and their postbiotics on Caco-2 cells. Microbial pathogenesis 17 36174833
2017 Hypomethylation of the Angiotensin II Type I Receptor (AGTR1) Gene Along with Environmental Factors Increases the Risk for Essential Hypertension. Cardiology 17 28376480
2008 Identification of the invariant chain (CD74) as an angiotensin AGTR1-interacting protein. The Journal of endocrinology 17 18719072
2007 Renal function dependent association of AGTR1 polymorphism (A1166C) and electrocardiographic left-ventricular hypertrophy. American journal of hypertension 17 17903694
2021 Increased AT1 receptor expression mediates vasoconstriction leading to hypertension in Snx1-/- mice. Hypertension research : official journal of the Japanese Society of Hypertension 16 33972750
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2012 Association of left ventricular mass with the AGTR1 A1166C polymorphism. American journal of hypertension 15 22237156
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