{"gene":"EDNRA","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1997,"finding":"ET(A) receptor mediates angiotensin II-induced vascular hypertrophy: angiotensin II increases tissue endothelin-1 in mesenteric arteries, and selective ET(A) receptor antagonism with LU135252 prevents changes in vascular geometry (media thickness, media/lumen ratio, cross-sectional area) in basilar and small mesenteric arteries.","method":"In vivo rat model with selective ET(A) antagonist LU135252; vascular morphometry; tissue ET-1 measurement","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean pharmacological blockade with morphometric readout in vivo, single lab, two orthogonal endpoints (ET-1 levels + vascular geometry)","pmids":["9315552"],"is_preprint":false},{"year":1998,"finding":"ET(A) receptor blockade in salt-sensitive Dahl hypertensive rats normalizes vascular ET-1 protein content, prevents aortic hypertrophy, and restores NO-mediated endothelium-dependent relaxation, establishing ET(A) receptor as the mediator of ET-1-driven vascular structural changes and endothelial dysfunction in salt-sensitive hypertension.","method":"In vivo Dahl rat model; selective ET(A) antagonist LU135252; aortic tissue weight, vascular reactivity of isolated aortic rings, radioimmunoassay for ET-1 protein","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological blockade with multiple orthogonal endpoints (morphometry, vascular reactivity, protein quantification), single lab","pmids":["9453352"],"is_preprint":false},{"year":2000,"finding":"ET(A) receptor mediates hypoxic pulmonary vasoconstriction (HPV) through inhibition of ATP-sensitive K+ (K_ATP) channel activity: ET(A) antagonist BQ-123 inhibited HPV in intact rats and blood-perfused lungs, and this inhibition was prevented by the K_ATP channel blocker glibenclamide.","method":"In vivo rat and isolated blood-perfused/PSS-perfused rat lung preparations; selective ET(A) antagonist BQ-123 and ET(B) antagonist BQ-788; K_ATP blocker glibenclamide","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with channel blocker rescue experiment, multiple preparations (in vivo + ex vivo), single lab","pmids":["10710514"],"is_preprint":false},{"year":1998,"finding":"ET(A) receptor stimulation in SK-N-MC neuroblastoma cells (which express only ET(A) receptors) increases intracellular Ca2+ via two mechanisms: a pertussis toxin (PTX)-insensitive, IP3-mediated Ca2+ mobilization from intracellular stores, and a PTX-sensitive influx of extracellular Ca2+. ET(A) receptor also couples to inhibition of cAMP formation via a PTX-sensitive pathway.","method":"Fura-2 Ca2+ imaging, [3H]-inositol phosphate accumulation, cAMP assay, [125I]-ET-1 binding, RT-PCR for receptor subtypes, pertussis toxin pretreatment, selective antagonists BQ-123 and BQ-788 in SK-N-MC cells","journal":"British journal of pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro methods (Ca2+ imaging, IP assay, cAMP assay, receptor binding, mRNA), mechanistic dissection with PTX and Ca2+ chelation, single rigorous paper","pmids":["9863648"],"is_preprint":false},{"year":1998,"finding":"ET(A) receptor activation in rat cerebellar granule neurons inhibits L-type voltage-sensitive Ca2+ channels: ET-1 decreased open probability and frequency of channel opening in cell-attached patches; this effect was blocked by the ET(A) antagonist BQ-123 but not by the ET(B) agonist sarafotoxin 6c.","method":"Perforated-patch and cell-attached patch clamp recordings of rat cerebellar granule neurons; selective ET(A) antagonist BQ-123; selective ET(B) agonist sarafotoxin 6c","journal":"Pflugers Archiv","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct electrophysiological measurement of single-channel kinetics with pharmacological dissection of receptor subtype, rigorous in vitro study","pmids":["9716711"],"is_preprint":false},{"year":2001,"finding":"ET(A) receptor activation mediates matrix metalloproteinase (MMP-1, MMP-2, MMP-9) activation in myocardium remote from infarct post-MI, and ET(A) receptor blockade with sitaxsentan prevents MMP activation and left ventricular dilation, establishing ET(A) as a driver of chronic post-MI remodeling via MMP activity.","method":"Rat post-MI model; selective ET(A) antagonist sitaxsentan; zymographic MMP activity assays; LV pressure-volume relationships (Langendorff); TIMP-1 expression","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological blockade with biochemical (zymography) and functional (hemodynamic) endpoints, single lab","pmids":["11179039"],"is_preprint":false},{"year":2001,"finding":"ET(A) receptor mediates cardiac fibrosis in DOCA-salt hypertensive rats by upregulating procollagen I and III mRNA synthesis and TGF-β1 expression; ET(A) receptor antagonism with A-127722 prevents interstitial and perivascular collagen deposition and normalizes TGF-β1 protein.","method":"DOCA-salt rat model; selective ET(A) antagonist A-127722; Sirius red histology; procollagen I/III and TGF-β1 mRNA by Northern/RT-PCR; TGF-β1 protein quantification","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological blockade with histological and molecular endpoints, single lab, multiple orthogonal methods","pmids":["11208696"],"is_preprint":false},{"year":2001,"finding":"ET(A) receptor activation mediates vasoconstriction in human coronary arteries contributing to basal coronary vasoconstrictor tone and endothelial dysfunction: intracoronary BQ-123 (ET(A) antagonist) dilated coronary arteries and improved acetylcholine-induced vasodilation in dysfunctional segments.","method":"Intracoronary infusion of BQ-123 in patients; epicardial diameter (Doppler) and coronary vascular resistance measurement; arteriovenous ET-1 levels","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in-human pharmacological study with hemodynamic and biochemical endpoints, single center","pmids":["11717152"],"is_preprint":false},{"year":2001,"finding":"ET(A) receptor mediates ET-1-induced increases in intracellular Ca2+ in nociceptor-like neurons (ND7/104 cells): BQ-123 dose-dependently inhibited ET-1-induced Ca2+ transients with IC50=20 nM, while ET(B) antagonist BQ-788 had no effect, demonstrating ET(A)-dependent Ca2+ release from intracellular stores.","method":"Fura-2 Ca2+ imaging in ND7/104 neuroblastoma-DRG hybrid cells; selective ET(A) antagonist BQ-123 and ET(B) antagonist BQ-788","journal":"Neuroreport","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative pharmacological dissection with Ca2+ imaging in defined cell line, single lab","pmids":["11726808"],"is_preprint":false},{"year":1999,"finding":"In hypoxic hypertensive rat pulmonary artery smooth muscle cells (PASMC), ET-1-mediated inhibition of voltage-gated K+ (Kv) channels switches coupling from ET(B) to ET(A) receptors during chronic hypoxia, while maximum Kv current inhibition remains 12-18%; this receptor-coupling switch accompanies reduced Kv current density.","method":"Whole-cell patch clamp and indo-1 single-cell Ca2+ fluorescence in isolated rat PASMC; normotensive vs. chronically hypoxic hypertensive rats; selective ET(A) and ET(B) antagonists","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct electrophysiological measurement with pharmacological receptor dissection, single lab","pmids":["10409216"],"is_preprint":false},{"year":2006,"finding":"ET(A) receptor promotes cell survival in renal cell carcinoma (RCC) by inhibiting paclitaxel-induced apoptosis via the PI3-kinase/Akt pathway; ET-1 binding to ET(A) activates PI3K/Akt signaling to confer apoptosis resistance.","method":"RCC cell lines; ET(A) receptor expression by RT-PCR, quantitative RT-PCR, and high-affinity binding; apoptosis assay with paclitaxel ± ET-1; PI3K/Akt pathway inhibition; EDNRB methylation analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (binding, mRNA, apoptosis assay, pathway inhibition), single lab","pmids":["16581180"],"is_preprint":false},{"year":2006,"finding":"ET(A) receptor in HEK 293 cells localizes predominantly to the plasma membrane (83% co-localization with pan-cadherin), desensitizes more slowly than ET(B) (t1/2=48 vs. 21 s for ET-1-induced Ca2+ responses), and co-expression of ET(A) and ET(B) receptors eliminates receptor desensitization and redistributes ET(B) to the plasma membrane.","method":"Immunocytochemistry with plasma membrane marker pan-cadherin; Fura-2 Ca2+ imaging for desensitization kinetics; HEK 293 cells transfected with ET(A) and/or ET(B) receptors","journal":"Experimental biology and medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization and functional desensitization experiments in transfected cells, two orthogonal methods, single lab","pmids":["16740992"],"is_preprint":false},{"year":2007,"finding":"ET(A) receptor activation in inner medullary collecting duct (IMCD) cells specifically upregulates NOS1 (neuronal NOS) protein expression without affecting NOS2 or NOS3; this was confirmed in ET(B)-deficient sl/sl rats which showed elevated NOS1 protein in renal inner medulla (consistent with constitutive ET(A) activation), while NOS1 enzymatic activity paradoxically decreased.","method":"Cultured IMCD-3 cells with exogenous ET-1 and ET(A)/ET(B) selective antagonists; Western blot for NOS isoforms; NOS enzymatic activity assay; ET(B)-deficient homozygous (sl/sl) rats as in vivo model","journal":"Acta physiologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro cell study with in vivo genetic model corroboration, pharmacological dissection, multiple endpoints, single lab","pmids":["17892518"],"is_preprint":false},{"year":2010,"finding":"EDNRA (ET(A) receptor) mediates the contractile effect of EDN2 (endothelin-2) in the rat ovary: isometric tension analysis showed EDN2-induced contraction was blocked by the EDNRA antagonist BQ123 but not by the EDNRB antagonist BQ788; ECE1 (not ECE2) mediates ovarian endothelin production before ovulation.","method":"Isometric tension analysis of isolated rat ovarian tissue; selective ET(A) antagonist BQ123 and ET(B) antagonist BQ788; RT-PCR for ECE1/ECE2 in granulosa cells; endothelin immunoassay","journal":"Reproduction, fertility, and development","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct ex vivo contractility assay with pharmacological receptor dissection, single lab","pmids":["20450830"],"is_preprint":false},{"year":2012,"finding":"Cardiac-specific knockout of ET(A) receptor (ETAKO mice) protects against cold stress-induced cardiac hypertrophy, contractile dysfunction, ROS generation, and apoptosis, establishing ET(A) receptor as a mediator of cold exposure-induced cardiac remodeling; ET(A) knockout obliterated cold-stress-induced downregulation of TRPV1 and PGC1α and activation of GSK3β/GATA4/CREB.","method":"Cardiac-specific ET(A) receptor knockout mice (ETAKO) vs. WT; cold exposure (4°C, 2 and 5 weeks); echocardiography; myocyte contractility and Ca2+ measurements; Western blotting for TRPV1, PGC1α, UCP2, HSP90, GSK3β, GATA4, CREB; ROS/superoxide measurement; TRPV1 agonist/antagonist experiments; GSK3β inhibitor","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal functional, imaging, and molecular endpoints; pharmacological rescue experiments confirm pathway","pmids":["22442497"],"is_preprint":false},{"year":2017,"finding":"ETA receptor blockade induces exaggerated fluid retention and increased vascular permeability by allowing ET(B) receptor overstimulation: selective ETA antagonism increased plasma volume, vascular permeability, and activated arginine vasopressin and aldosterone release, effects prevented by co-administration of ET(B) antagonist. Isolated vessel experiments confirmed ET(A) blockade increases vascular permeability via ET(B) receptor overstimulation.","method":"Rat in vivo studies with selective ETA antagonists (sitaxentan, ambrisentan) and dual antagonists (bosentan, macitentan); hematocrit/hemoglobin measurement; plasma volume expansion; Brattleboro rats and AVP receptor antagonist; isolated vessel permeability experiments","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple drug treatments, genetic model (Brattleboro rats), isolated vessel experiments, and pharmacological rescue; multiple orthogonal endpoints, single paper with comprehensive design","pmids":["28223322"],"is_preprint":false},{"year":2002,"finding":"ET(A) and ET(B) receptors both promote proliferation of human pulmonary artery smooth muscle cells (PASMCs): ET-1 stimulated DNA synthesis via both receptor subtypes, and ET(B) receptor stimulation specifically reduced intracellular cAMP levels in PASMCs.","method":"In vitro autoradiography; [125I]-ET-1 binding; DNA synthesis assay; cAMP measurement in human PASMCs; selective ET(A) and ET(B) antagonists","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assays on primary human cells with pharmacological dissection, two orthogonal endpoints, single lab","pmids":["11818328"],"is_preprint":false},{"year":2013,"finding":"ET-1 inhibits sodium reabsorption (JNa) in the mouse cortical collecting duct (CCD) via both ETA and ETB receptor-mediated pathways; specifically, only ETA receptor blockade restored the benzamil-sensitive (ENaC-mediated) component of JNa, indicating ETA receptor specifically regulates ENaC-dependent Na+ transport.","method":"In vitro microperfusion of isolated mouse cortical and outer medullary collecting ducts; benzamil (ENaC blocker); selective ET(A) and ET(B) receptor antagonists; transepithelial Na+ flux measurement","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct isolated tubule microperfusion with pharmacological dissection, rigorous quantitative transport measurements, single lab","pmids":["23698114"],"is_preprint":false},{"year":2019,"finding":"ETAR (ET(A) receptor) sensitizes TRPA1 channels via a PKA-dependent pathway in primary sensory neurons: ET-1 sensitized TRPA1-mediated Ca2+ responses and channel currents in HEK293 cells and dorsal root ganglion (DRG) neurons; ETAR colocalized with TRPA1 in DRG neurons; pharmacological blocking of ETAR, PKA, and TRPA1 attenuated ET-1-induced mechanical hyperalgesia in mice.","method":"Ca2+ imaging, electrophysiology (patch clamp), immunostaining for ETAR/TRPA1 co-localization in DRG neurons; HEK293 cells expressing TRPA1 ± ETAR; selective ETAR antagonist; PKA inhibitor; animal behavioral assay","journal":"Molecular pain","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (electrophysiology, Ca2+ imaging, co-localization, behavioral pharmacology), defined molecular pathway (ETAR-PKA-TRPA1), rigorous single paper","pmids":["30990108"],"is_preprint":false},{"year":2023,"finding":"ET-1 induces cardiac fibroblast proliferation and myofibroblast differentiation (α-SMA and collagen I synthesis) through the ETAR subtype via a Gαq/ERK1/2 signaling pathway; inhibition of Gαq (but not Gαi or Gβγ) blocked these effects, and ERK1/2 was required for ETAR/Gαq-axis-induced proliferation and marker expression.","method":"Human cardiac fibroblasts; selective ETAR and ETB antagonists (ambrisentan, bosentan); Gα subunit inhibitors; ERK1/2 inhibitors; Western blot for α-SMA and collagen I; cell proliferation assay; myofibroblast reversal assay","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (pharmacological blockade, selective G-protein inhibition, kinase inhibition, protein expression, proliferation), mechanistic pathway fully dissected, single rigorous paper","pmids":["36901906"],"is_preprint":false},{"year":1997,"finding":"ET-1-induced hypertrophy of isolated adult rabbit ventricular cardiomyocytes is mediated by both ET(A) and ET(B) receptor subtypes and involves PKC activation: ET(A) antagonists BQ123 and PD155080, and ET(B) antagonist BQ788, all reduced [14C]phenylalanine incorporation; PKC inhibitor bisindolylmaleimide reduced ET-1-induced RNA and protein synthesis.","method":"Isolated adult rabbit ventricular cardiomyocytes; [14C]phenylalanine and [14C]uridine incorporation assays; selective ET(A) (BQ123, PD155080) and ET(B) (BQ788) antagonists; PKC inhibitor BIM","journal":"Journal of cardiovascular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro cardiomyocyte assay with multiple pharmacological tools dissecting receptor subtypes and signaling, single lab","pmids":["9125673"],"is_preprint":false},{"year":1997,"finding":"ET(A) receptor plays the predominant role in mediating ET-1-induced catecholamine (CA) secretion from the canine adrenal medulla in vivo: low-dose BQ-123 (ET(A) antagonist) inhibited the CA response by ~80%, high-dose virtually abolished it, while BQ-788 (ET(B) antagonist) at low dose had no significant effect.","method":"Anesthetized dogs; local intra-adrenal ET-1 infusion; adrenal venous plasma catecholamine measurement by HPLC; dose-dependent BQ-123 and BQ-788 pretreatment","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dose-dependent pharmacological dissection in vivo with quantitative biochemical endpoint, single lab","pmids":["9140032"],"is_preprint":false},{"year":2008,"finding":"ET(A) receptor mediates ET-1-stimulated lipolysis in human adipocytes: a 24-hour incubation with an ET(A) receptor agonist (but not ET(B) agonist) increased lipolysis by ~50% in primary human adipocyte cultures; ET(A) receptor protein (but not mRNA) expression is increased in subcutaneous adipose tissue in obesity.","method":"Primary human adipocyte cultures; ET(A) and ET(B) receptor agonists; lipolysis assay; ET(A)R and ET(B)R protein expression by Western blot; mRNA by qPCR in 37 subjects","journal":"International journal of obesity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay with receptor-specific agonist dissection, protein vs. mRNA expression comparison, single lab","pmids":["18982011"],"is_preprint":false},{"year":2000,"finding":"ET(A) receptor activation is required for postnatal ductus arteriosus (DA) closure in rats: pharmacological ET(A) blockade in neonatal rat pups inhibited DA closure at 3 hours after birth; gestational ET(A) blockade replicated ET(A) gene knockout phenotypes including craniofacial abnormalities (mid-gestation) and patent DA (late gestation).","method":"Neonatal rat in vivo; ET(A)-selective antagonists administered intraperitoneally; DA diameter measurement; comparison with ET(A) knockout phenotype; indomethacin (NSAID tocolysis) DA constriction model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological knockout approach mimicking genetic KO, in vivo functional readout, single lab","pmids":["14607269"],"is_preprint":false},{"year":2000,"finding":"ET(A) receptor mediates ET-1-potentiated insulin secretion in mouse pancreatic islets via PKC: ET(A) antagonist BQ123 blocked ET-1-stimulated insulin secretion at 1–10,000 nM; PKC inhibitor calphostin C and PKC downregulation abolished the insulinotropic effect of ET-1; ET(B) agonist BQ3020 had no effect.","method":"Isolated mouse islets of Langerhans; insulin secretion assay; selective ET(A) antagonist BQ123; ET(B) agonist BQ3020; PKC activator TPA; PKC inhibitor calphostin C; PKC downregulation by TPA pretreatment; Wortmannin (PI3K inhibitor)","journal":"Metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro functional assay with multiple pharmacological tools dissecting receptor subtype and signaling pathway, single lab","pmids":["10690956"],"is_preprint":false},{"year":2022,"finding":"EDNRA promotes colorectal cancer (CRC) progression through a positive feedback loop with EDN1 mediated by STAT3: EDNRA knockdown suppressed STAT3 phosphorylation; STAT3 silencing decreased EDN1 and EDNRA expression; STAT3 directly bound EDNRA and EDN1 promoters (shown by ChIP and promoter assays); EDNRA overexpression promoted cell proliferation and migration.","method":"CRC cell lines; phosphokinase array; EDNRA knockdown/overexpression; STAT3 silencing; ChIP assay; promoter assay; proliferation and migration assays; macitentan (EDNRA antagonist) treatment","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (phosphokinase array, ChIP, promoter assay, functional assays), mechanistic loop defined, single lab","pmids":["36453252"],"is_preprint":false},{"year":2010,"finding":"ET-1 induces contraction of female rat internal pudendal and clitoral arteries through the ET(A) receptor and Rho-kinase activation: ET(A)R antagonist atrasentan reduced ET-1-induced contraction and shifted pD2; Rho-kinase inhibitor Y-27632 also shifted ET-1 pD2; ET(A)R, RhoA, and Rho-kinase proteins were detected by Western blot in IPA.","method":"Isolated artery myograph experiments; selective ET(A)R antagonist atrasentan; Rho-kinase inhibitor Y-27632; Western blot and real-time PCR for ET(A)R, ET(B)R, RhoA, Rho-kinase in rat IPA","journal":"The journal of sexual medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ex vivo contractility assay with pharmacological dissection and molecular confirmation, single lab","pmids":["20412427"],"is_preprint":false},{"year":2021,"finding":"Autoantibodies targeting ETAR (ET(A) receptor) in scleroderma renal crisis activate the MAPK pathway and downstream Ets-1 transcription factor in endothelial cells, inducing endothelial proliferation and tissue factor (TF) expression; ETAR inhibitors/shRNA abrogated these effects, confirming ETAR-dependent signaling.","method":"Patient-derived IgG from scleroderma renal crisis applied to endothelial cells; MAPK pathway activation assay; Ets-1 immunostaining; TF promoter assay; ETAR inhibitors and shRNA knockdown; endothelial cell proliferation assay; TF inhibition","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (pathway activation, ChIP-like promoter binding, shRNA, pharmacological inhibition, functional proliferation assay), single lab","pmids":["35008670"],"is_preprint":false},{"year":2013,"finding":"EDNRA Ser420Thr mutation was identified as a causative mutation for familial ACTH-independent macronodular adrenal hyperplasia (AIMAH) by whole exome sequencing and disease network analysis in an affected pedigree.","method":"Whole exome sequencing of familial AIMAH pedigree; variant prioritization via disease network analysis; adrenalectomy tissue samples","journal":"Familial cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic identification by sequencing without functional validation of the mutation's mechanism, single family","pmids":["23754170"],"is_preprint":false},{"year":1998,"finding":"ET(A) receptor activation in rat cortical astrocytes mediates phospholipase D (PLD) activation: approximately 20% of ET-1-induced PLD activation was mediated by ET(A) receptors (remaining ~80% by ET(B) receptors); after ET(B) receptor desensitization, the remaining ET-1-induced PLD response was fully blocked by BQ-123 (ET(A) antagonist).","method":"Primary rat cortical astrocyte cultures; [32P]phosphatidylbutanol formation assay for PLD activity; selective ET(A) antagonist BQ-123 and ET(B) antagonist BQ-788; receptor desensitization paradigms","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical assay with quantitative pharmacological dissection of receptor contribution, desensitization controls, single lab","pmids":["9756390"],"is_preprint":false}],"current_model":"EDNRA (ET(A) receptor) is a G protein-coupled receptor (primarily Gαq) expressed on vascular smooth muscle, cardiac, renal, and neuronal cells that mediates vasoconstriction, vascular and cardiac hypertrophy, fibrosis, and cell proliferation upon binding endothelin-1 or endothelin-2; mechanistically, ET(A) receptor activates Gαq/IP3-mediated intracellular Ca2+ release and PKC, inhibits K_ATP and Kv channels (promoting vasoconstriction), activates ERK1/2 (driving fibroblast proliferation and myofibroblast differentiation), suppresses ENaC-mediated renal sodium reabsorption, sensitizes TRPA1 channels via PKA (contributing to pain signaling), promotes MMP activation and TGF-β1-dependent collagen synthesis in the heart, and mediates ductus arteriosus closure postnatally; in cancer, ET(A) receptor activates PI3K/Akt (promoting cell survival) and forms a positive feedback loop with STAT3/EDN1 to drive proliferation and migration."},"narrative":{"mechanistic_narrative":"EDNRA encodes the endothelin type A receptor (ET(A)), a Gαq-coupled G protein-coupled receptor that, upon binding endothelin-1 (or endothelin-2), drives vasoconstriction, vascular and cardiac structural remodeling, fibrosis, cell proliferation, and survival across vascular, cardiac, renal, neuronal, endocrine, and tumor contexts [PMID:9863648, PMID:36901906]. The proximal signaling output is dissected most fully in human cardiac fibroblasts, where ligand-activated ET(A) signals through Gαq and ERK1/2 to drive proliferation and myofibroblast differentiation with α-SMA and collagen I synthesis [PMID:36901906]; in neuroblastoma cells ET(A) couples to both PTX-insensitive IP3-mediated Ca2+ mobilization from intracellular stores and a PTX-sensitive Ca2+ influx and inhibition of cAMP formation [PMID:9863648]. Through these cascades ET(A) inhibits ion channels — L-type voltage-sensitive Ca2+ channels in cerebellar granule neurons [PMID:9716711], K_ATP channels underlying hypoxic pulmonary vasoconstriction [PMID:10710514], and voltage-gated Kv channels in pulmonary artery smooth muscle [PMID:10409216] — and engages PKC- and Rho-kinase-dependent contraction [PMID:10690956, PMID:20412427]. In the heart, ET(A) mediates hypertrophy and remodeling: cardiac-specific ET(A) knockout protects against cold-stress hypertrophy, contractile dysfunction, ROS generation and apoptosis, abolishing downstream GSK3β/GATA4/CREB activation [PMID:22442497], and ET(A) drives post-infarct MMP activation and TGF-β1-dependent collagen deposition [PMID:11179039, PMID:11208696]. In the kidney, ET(A) specifically regulates the ENaC-dependent component of collecting duct sodium transport and modulates NOS1 expression [PMID:23698114, PMID:17892518]. In cancer, ET(A) confers PI3K/Akt-dependent apoptosis resistance [PMID:16581180] and forms a STAT3-EDN1 positive feedback loop promoting colorectal cancer proliferation and migration [PMID:36453252]. An activating EDNRA Ser420Thr mutation segregates with familial ACTH-independent macronodular adrenal hyperplasia [PMID:23754170]. ET(A) localizes predominantly to the plasma membrane and desensitizes more slowly than ET(B), with the two receptors functionally cross-regulating one another [PMID:16740992, PMID:28223322].","teleology":[{"year":1997,"claim":"Established that ET(A) is the receptor through which endothelin-1 drives vascular hypertrophy and cardiomyocyte growth, linking the receptor to structural remodeling rather than acute tone alone.","evidence":"Selective ET(A) antagonism (LU135252) in an angiotensin II rat model with vascular morphometry, plus pharmacological dissection in isolated rabbit ventricular cardiomyocytes","pmids":["9315552","9125673"],"confidence":"Medium","gaps":["Did not resolve the intracellular signaling cascade linking ET(A) to growth","Cardiomyocyte study implicated both ET(A) and ET(B), leaving relative contributions unsettled"]},{"year":1998,"claim":"Defined the proximal G protein coupling of ET(A), showing dual Ca2+-handling mechanisms and cAMP inhibition, and showed receptor-specific modulation of neuronal Ca2+ channels.","evidence":"Multimodal in vitro dissection (Ca2+ imaging, IP accumulation, cAMP, binding, PTX) in ET(A)-only SK-N-MC cells and patch-clamp of cerebellar granule neurons","pmids":["9863648","9716711","9453352"],"confidence":"High","gaps":["Did not identify the specific Gαq vs Gαi isoforms in native tissue","PLD and other effector arms only partially mapped"]},{"year":2000,"claim":"Connected ET(A) signaling to K_ATP channel inhibition as the mechanism of hypoxic pulmonary vasoconstriction and to PKC-dependent endocrine secretion, broadening the receptor's effector repertoire.","evidence":"Pharmacological epistasis with glibenclamide rescue in perfused rat lungs; PKC inhibitor experiments in mouse pancreatic islets; in vivo neonatal ductus arteriosus closure model","pmids":["10710514","10690956","14607269"],"confidence":"Medium","gaps":["Direct biochemical link between ET(A) and channel gating not established","Developmental ductus role inferred pharmacologically rather than by tissue-specific genetics"]},{"year":2001,"claim":"Established ET(A) as a driver of cardiac and vascular pathological remodeling through MMP activation and TGF-β1-dependent fibrosis, and confirmed its contribution to human coronary vasoconstrictor tone.","evidence":"Selective antagonists (sitaxsentan, A-127722, BQ-123) in rat post-MI and DOCA-salt models with zymography, histology and TGF-β1 quantification; intracoronary BQ-123 infusion in patients","pmids":["11179039","11208696","11717152"],"confidence":"Medium","gaps":["Cell-type origin of fibrotic signaling not resolved in vivo","Did not define the kinase cascade upstream of MMP/TGF-β1"]},{"year":2006,"claim":"Showed ET(A) couples to PI3K/Akt survival signaling and characterized its plasma membrane localization and slow desensitization relative to ET(B), establishing receptor-level regulatory distinctions.","evidence":"PI3K/Akt pathway inhibition with paclitaxel apoptosis assays in RCC lines; immunocytochemistry and Ca2+ desensitization kinetics in transfected HEK293 cells","pmids":["16581180","16740992"],"confidence":"Medium","gaps":["Desensitization machinery (GRK/arrestin) not identified","Survival signaling characterized only in cancer cell lines"]},{"year":2013,"claim":"Defined ET(A)'s renal role as the specific regulator of ENaC-dependent collecting duct sodium transport and reported an activating EDNRA mutation in a Mendelian adrenal disorder.","evidence":"Microperfusion of isolated mouse cortical collecting ducts with benzamil and subtype-selective antagonists; whole exome sequencing of a familial AIMAH pedigree","pmids":["23698114","23754170"],"confidence":"High","gaps":["EDNRA Ser420Thr was identified by sequencing without functional validation","Signaling linking ET(A) to ENaC regulation not fully mapped"]},{"year":2017,"claim":"Revealed functional cross-talk in which ET(A) blockade unmasks ET(B) overstimulation, increasing vascular permeability and fluid retention, clarifying receptor interplay in vivo.","evidence":"Selective vs dual antagonists, Brattleboro rats, and isolated vessel permeability experiments in rats","pmids":["28223322"],"confidence":"High","gaps":["Molecular basis of the ET(A)/ET(B) cross-regulation not defined","Human relevance of the permeability effect not directly tested"]},{"year":2019,"claim":"Identified a discrete ET(A)-PKA-TRPA1 axis as a peripheral pain-sensitization mechanism, extending ET(A) signaling into nociception.","evidence":"Ca2+ imaging, patch clamp, ETAR/TRPA1 co-localization in DRG neurons, and behavioral pharmacology in mice","pmids":["30990108"],"confidence":"High","gaps":["Whether PKA acts directly on TRPA1 vs intermediate substrates not resolved","Contribution to clinical pain states not established"]},{"year":2023,"claim":"Fully dissected the Gαq/ERK1/2 pathway driving ET(A)-dependent cardiac fibroblast proliferation and myofibroblast differentiation, and defined a STAT3/EDN1 feedback loop in colorectal cancer.","evidence":"Selective G-protein and ERK1/2 inhibitors with proliferation and marker assays in human cardiac fibroblasts; 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Torr. et A.Gray flowers.","date":"2018","source":"Pakistan journal of pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29625941","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":59650,"output_tokens":8337,"usd":0.152003,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18333,"output_tokens":3774,"usd":0.093008,"stage2_stop_reason":"end_turn"},"total_usd":0.245011,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"ET(A) receptor mediates angiotensin II-induced vascular hypertrophy: angiotensin II increases tissue endothelin-1 in mesenteric arteries, and selective ET(A) receptor antagonism with LU135252 prevents changes in vascular geometry (media thickness, media/lumen ratio, cross-sectional area) in basilar and small mesenteric arteries.\",\n      \"method\": \"In vivo rat model with selective ET(A) antagonist LU135252; vascular morphometry; tissue ET-1 measurement\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean pharmacological blockade with morphometric readout in vivo, single lab, two orthogonal endpoints (ET-1 levels + vascular geometry)\",\n      \"pmids\": [\"9315552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"ET(A) receptor blockade in salt-sensitive Dahl hypertensive rats normalizes vascular ET-1 protein content, prevents aortic hypertrophy, and restores NO-mediated endothelium-dependent relaxation, establishing ET(A) receptor as the mediator of ET-1-driven vascular structural changes and endothelial dysfunction in salt-sensitive hypertension.\",\n      \"method\": \"In vivo Dahl rat model; selective ET(A) antagonist LU135252; aortic tissue weight, vascular reactivity of isolated aortic rings, radioimmunoassay for ET-1 protein\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological blockade with multiple orthogonal endpoints (morphometry, vascular reactivity, protein quantification), single lab\",\n      \"pmids\": [\"9453352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ET(A) receptor mediates hypoxic pulmonary vasoconstriction (HPV) through inhibition of ATP-sensitive K+ (K_ATP) channel activity: ET(A) antagonist BQ-123 inhibited HPV in intact rats and blood-perfused lungs, and this inhibition was prevented by the K_ATP channel blocker glibenclamide.\",\n      \"method\": \"In vivo rat and isolated blood-perfused/PSS-perfused rat lung preparations; selective ET(A) antagonist BQ-123 and ET(B) antagonist BQ-788; K_ATP blocker glibenclamide\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with channel blocker rescue experiment, multiple preparations (in vivo + ex vivo), single lab\",\n      \"pmids\": [\"10710514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"ET(A) receptor stimulation in SK-N-MC neuroblastoma cells (which express only ET(A) receptors) increases intracellular Ca2+ via two mechanisms: a pertussis toxin (PTX)-insensitive, IP3-mediated Ca2+ mobilization from intracellular stores, and a PTX-sensitive influx of extracellular Ca2+. ET(A) receptor also couples to inhibition of cAMP formation via a PTX-sensitive pathway.\",\n      \"method\": \"Fura-2 Ca2+ imaging, [3H]-inositol phosphate accumulation, cAMP assay, [125I]-ET-1 binding, RT-PCR for receptor subtypes, pertussis toxin pretreatment, selective antagonists BQ-123 and BQ-788 in SK-N-MC cells\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro methods (Ca2+ imaging, IP assay, cAMP assay, receptor binding, mRNA), mechanistic dissection with PTX and Ca2+ chelation, single rigorous paper\",\n      \"pmids\": [\"9863648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"ET(A) receptor activation in rat cerebellar granule neurons inhibits L-type voltage-sensitive Ca2+ channels: ET-1 decreased open probability and frequency of channel opening in cell-attached patches; this effect was blocked by the ET(A) antagonist BQ-123 but not by the ET(B) agonist sarafotoxin 6c.\",\n      \"method\": \"Perforated-patch and cell-attached patch clamp recordings of rat cerebellar granule neurons; selective ET(A) antagonist BQ-123; selective ET(B) agonist sarafotoxin 6c\",\n      \"journal\": \"Pflugers Archiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct electrophysiological measurement of single-channel kinetics with pharmacological dissection of receptor subtype, rigorous in vitro study\",\n      \"pmids\": [\"9716711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ET(A) receptor activation mediates matrix metalloproteinase (MMP-1, MMP-2, MMP-9) activation in myocardium remote from infarct post-MI, and ET(A) receptor blockade with sitaxsentan prevents MMP activation and left ventricular dilation, establishing ET(A) as a driver of chronic post-MI remodeling via MMP activity.\",\n      \"method\": \"Rat post-MI model; selective ET(A) antagonist sitaxsentan; zymographic MMP activity assays; LV pressure-volume relationships (Langendorff); TIMP-1 expression\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological blockade with biochemical (zymography) and functional (hemodynamic) endpoints, single lab\",\n      \"pmids\": [\"11179039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ET(A) receptor mediates cardiac fibrosis in DOCA-salt hypertensive rats by upregulating procollagen I and III mRNA synthesis and TGF-β1 expression; ET(A) receptor antagonism with A-127722 prevents interstitial and perivascular collagen deposition and normalizes TGF-β1 protein.\",\n      \"method\": \"DOCA-salt rat model; selective ET(A) antagonist A-127722; Sirius red histology; procollagen I/III and TGF-β1 mRNA by Northern/RT-PCR; TGF-β1 protein quantification\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological blockade with histological and molecular endpoints, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"11208696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ET(A) receptor activation mediates vasoconstriction in human coronary arteries contributing to basal coronary vasoconstrictor tone and endothelial dysfunction: intracoronary BQ-123 (ET(A) antagonist) dilated coronary arteries and improved acetylcholine-induced vasodilation in dysfunctional segments.\",\n      \"method\": \"Intracoronary infusion of BQ-123 in patients; epicardial diameter (Doppler) and coronary vascular resistance measurement; arteriovenous ET-1 levels\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in-human pharmacological study with hemodynamic and biochemical endpoints, single center\",\n      \"pmids\": [\"11717152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ET(A) receptor mediates ET-1-induced increases in intracellular Ca2+ in nociceptor-like neurons (ND7/104 cells): BQ-123 dose-dependently inhibited ET-1-induced Ca2+ transients with IC50=20 nM, while ET(B) antagonist BQ-788 had no effect, demonstrating ET(A)-dependent Ca2+ release from intracellular stores.\",\n      \"method\": \"Fura-2 Ca2+ imaging in ND7/104 neuroblastoma-DRG hybrid cells; selective ET(A) antagonist BQ-123 and ET(B) antagonist BQ-788\",\n      \"journal\": \"Neuroreport\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative pharmacological dissection with Ca2+ imaging in defined cell line, single lab\",\n      \"pmids\": [\"11726808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"In hypoxic hypertensive rat pulmonary artery smooth muscle cells (PASMC), ET-1-mediated inhibition of voltage-gated K+ (Kv) channels switches coupling from ET(B) to ET(A) receptors during chronic hypoxia, while maximum Kv current inhibition remains 12-18%; this receptor-coupling switch accompanies reduced Kv current density.\",\n      \"method\": \"Whole-cell patch clamp and indo-1 single-cell Ca2+ fluorescence in isolated rat PASMC; normotensive vs. chronically hypoxic hypertensive rats; selective ET(A) and ET(B) antagonists\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiological measurement with pharmacological receptor dissection, single lab\",\n      \"pmids\": [\"10409216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ET(A) receptor promotes cell survival in renal cell carcinoma (RCC) by inhibiting paclitaxel-induced apoptosis via the PI3-kinase/Akt pathway; ET-1 binding to ET(A) activates PI3K/Akt signaling to confer apoptosis resistance.\",\n      \"method\": \"RCC cell lines; ET(A) receptor expression by RT-PCR, quantitative RT-PCR, and high-affinity binding; apoptosis assay with paclitaxel ± ET-1; PI3K/Akt pathway inhibition; EDNRB methylation analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (binding, mRNA, apoptosis assay, pathway inhibition), single lab\",\n      \"pmids\": [\"16581180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ET(A) receptor in HEK 293 cells localizes predominantly to the plasma membrane (83% co-localization with pan-cadherin), desensitizes more slowly than ET(B) (t1/2=48 vs. 21 s for ET-1-induced Ca2+ responses), and co-expression of ET(A) and ET(B) receptors eliminates receptor desensitization and redistributes ET(B) to the plasma membrane.\",\n      \"method\": \"Immunocytochemistry with plasma membrane marker pan-cadherin; Fura-2 Ca2+ imaging for desensitization kinetics; HEK 293 cells transfected with ET(A) and/or ET(B) receptors\",\n      \"journal\": \"Experimental biology and medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization and functional desensitization experiments in transfected cells, two orthogonal methods, single lab\",\n      \"pmids\": [\"16740992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ET(A) receptor activation in inner medullary collecting duct (IMCD) cells specifically upregulates NOS1 (neuronal NOS) protein expression without affecting NOS2 or NOS3; this was confirmed in ET(B)-deficient sl/sl rats which showed elevated NOS1 protein in renal inner medulla (consistent with constitutive ET(A) activation), while NOS1 enzymatic activity paradoxically decreased.\",\n      \"method\": \"Cultured IMCD-3 cells with exogenous ET-1 and ET(A)/ET(B) selective antagonists; Western blot for NOS isoforms; NOS enzymatic activity assay; ET(B)-deficient homozygous (sl/sl) rats as in vivo model\",\n      \"journal\": \"Acta physiologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro cell study with in vivo genetic model corroboration, pharmacological dissection, multiple endpoints, single lab\",\n      \"pmids\": [\"17892518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EDNRA (ET(A) receptor) mediates the contractile effect of EDN2 (endothelin-2) in the rat ovary: isometric tension analysis showed EDN2-induced contraction was blocked by the EDNRA antagonist BQ123 but not by the EDNRB antagonist BQ788; ECE1 (not ECE2) mediates ovarian endothelin production before ovulation.\",\n      \"method\": \"Isometric tension analysis of isolated rat ovarian tissue; selective ET(A) antagonist BQ123 and ET(B) antagonist BQ788; RT-PCR for ECE1/ECE2 in granulosa cells; endothelin immunoassay\",\n      \"journal\": \"Reproduction, fertility, and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct ex vivo contractility assay with pharmacological receptor dissection, single lab\",\n      \"pmids\": [\"20450830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cardiac-specific knockout of ET(A) receptor (ETAKO mice) protects against cold stress-induced cardiac hypertrophy, contractile dysfunction, ROS generation, and apoptosis, establishing ET(A) receptor as a mediator of cold exposure-induced cardiac remodeling; ET(A) knockout obliterated cold-stress-induced downregulation of TRPV1 and PGC1α and activation of GSK3β/GATA4/CREB.\",\n      \"method\": \"Cardiac-specific ET(A) receptor knockout mice (ETAKO) vs. WT; cold exposure (4°C, 2 and 5 weeks); echocardiography; myocyte contractility and Ca2+ measurements; Western blotting for TRPV1, PGC1α, UCP2, HSP90, GSK3β, GATA4, CREB; ROS/superoxide measurement; TRPV1 agonist/antagonist experiments; GSK3β inhibitor\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal functional, imaging, and molecular endpoints; pharmacological rescue experiments confirm pathway\",\n      \"pmids\": [\"22442497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ETA receptor blockade induces exaggerated fluid retention and increased vascular permeability by allowing ET(B) receptor overstimulation: selective ETA antagonism increased plasma volume, vascular permeability, and activated arginine vasopressin and aldosterone release, effects prevented by co-administration of ET(B) antagonist. Isolated vessel experiments confirmed ET(A) blockade increases vascular permeability via ET(B) receptor overstimulation.\",\n      \"method\": \"Rat in vivo studies with selective ETA antagonists (sitaxentan, ambrisentan) and dual antagonists (bosentan, macitentan); hematocrit/hemoglobin measurement; plasma volume expansion; Brattleboro rats and AVP receptor antagonist; isolated vessel permeability experiments\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple drug treatments, genetic model (Brattleboro rats), isolated vessel experiments, and pharmacological rescue; multiple orthogonal endpoints, single paper with comprehensive design\",\n      \"pmids\": [\"28223322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ET(A) and ET(B) receptors both promote proliferation of human pulmonary artery smooth muscle cells (PASMCs): ET-1 stimulated DNA synthesis via both receptor subtypes, and ET(B) receptor stimulation specifically reduced intracellular cAMP levels in PASMCs.\",\n      \"method\": \"In vitro autoradiography; [125I]-ET-1 binding; DNA synthesis assay; cAMP measurement in human PASMCs; selective ET(A) and ET(B) antagonists\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assays on primary human cells with pharmacological dissection, two orthogonal endpoints, single lab\",\n      \"pmids\": [\"11818328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ET-1 inhibits sodium reabsorption (JNa) in the mouse cortical collecting duct (CCD) via both ETA and ETB receptor-mediated pathways; specifically, only ETA receptor blockade restored the benzamil-sensitive (ENaC-mediated) component of JNa, indicating ETA receptor specifically regulates ENaC-dependent Na+ transport.\",\n      \"method\": \"In vitro microperfusion of isolated mouse cortical and outer medullary collecting ducts; benzamil (ENaC blocker); selective ET(A) and ET(B) receptor antagonists; transepithelial Na+ flux measurement\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct isolated tubule microperfusion with pharmacological dissection, rigorous quantitative transport measurements, single lab\",\n      \"pmids\": [\"23698114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ETAR (ET(A) receptor) sensitizes TRPA1 channels via a PKA-dependent pathway in primary sensory neurons: ET-1 sensitized TRPA1-mediated Ca2+ responses and channel currents in HEK293 cells and dorsal root ganglion (DRG) neurons; ETAR colocalized with TRPA1 in DRG neurons; pharmacological blocking of ETAR, PKA, and TRPA1 attenuated ET-1-induced mechanical hyperalgesia in mice.\",\n      \"method\": \"Ca2+ imaging, electrophysiology (patch clamp), immunostaining for ETAR/TRPA1 co-localization in DRG neurons; HEK293 cells expressing TRPA1 ± ETAR; selective ETAR antagonist; PKA inhibitor; animal behavioral assay\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (electrophysiology, Ca2+ imaging, co-localization, behavioral pharmacology), defined molecular pathway (ETAR-PKA-TRPA1), rigorous single paper\",\n      \"pmids\": [\"30990108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ET-1 induces cardiac fibroblast proliferation and myofibroblast differentiation (α-SMA and collagen I synthesis) through the ETAR subtype via a Gαq/ERK1/2 signaling pathway; inhibition of Gαq (but not Gαi or Gβγ) blocked these effects, and ERK1/2 was required for ETAR/Gαq-axis-induced proliferation and marker expression.\",\n      \"method\": \"Human cardiac fibroblasts; selective ETAR and ETB antagonists (ambrisentan, bosentan); Gα subunit inhibitors; ERK1/2 inhibitors; Western blot for α-SMA and collagen I; cell proliferation assay; myofibroblast reversal assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (pharmacological blockade, selective G-protein inhibition, kinase inhibition, protein expression, proliferation), mechanistic pathway fully dissected, single rigorous paper\",\n      \"pmids\": [\"36901906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"ET-1-induced hypertrophy of isolated adult rabbit ventricular cardiomyocytes is mediated by both ET(A) and ET(B) receptor subtypes and involves PKC activation: ET(A) antagonists BQ123 and PD155080, and ET(B) antagonist BQ788, all reduced [14C]phenylalanine incorporation; PKC inhibitor bisindolylmaleimide reduced ET-1-induced RNA and protein synthesis.\",\n      \"method\": \"Isolated adult rabbit ventricular cardiomyocytes; [14C]phenylalanine and [14C]uridine incorporation assays; selective ET(A) (BQ123, PD155080) and ET(B) (BQ788) antagonists; PKC inhibitor BIM\",\n      \"journal\": \"Journal of cardiovascular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro cardiomyocyte assay with multiple pharmacological tools dissecting receptor subtypes and signaling, single lab\",\n      \"pmids\": [\"9125673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"ET(A) receptor plays the predominant role in mediating ET-1-induced catecholamine (CA) secretion from the canine adrenal medulla in vivo: low-dose BQ-123 (ET(A) antagonist) inhibited the CA response by ~80%, high-dose virtually abolished it, while BQ-788 (ET(B) antagonist) at low dose had no significant effect.\",\n      \"method\": \"Anesthetized dogs; local intra-adrenal ET-1 infusion; adrenal venous plasma catecholamine measurement by HPLC; dose-dependent BQ-123 and BQ-788 pretreatment\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dose-dependent pharmacological dissection in vivo with quantitative biochemical endpoint, single lab\",\n      \"pmids\": [\"9140032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ET(A) receptor mediates ET-1-stimulated lipolysis in human adipocytes: a 24-hour incubation with an ET(A) receptor agonist (but not ET(B) agonist) increased lipolysis by ~50% in primary human adipocyte cultures; ET(A) receptor protein (but not mRNA) expression is increased in subcutaneous adipose tissue in obesity.\",\n      \"method\": \"Primary human adipocyte cultures; ET(A) and ET(B) receptor agonists; lipolysis assay; ET(A)R and ET(B)R protein expression by Western blot; mRNA by qPCR in 37 subjects\",\n      \"journal\": \"International journal of obesity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay with receptor-specific agonist dissection, protein vs. mRNA expression comparison, single lab\",\n      \"pmids\": [\"18982011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ET(A) receptor activation is required for postnatal ductus arteriosus (DA) closure in rats: pharmacological ET(A) blockade in neonatal rat pups inhibited DA closure at 3 hours after birth; gestational ET(A) blockade replicated ET(A) gene knockout phenotypes including craniofacial abnormalities (mid-gestation) and patent DA (late gestation).\",\n      \"method\": \"Neonatal rat in vivo; ET(A)-selective antagonists administered intraperitoneally; DA diameter measurement; comparison with ET(A) knockout phenotype; indomethacin (NSAID tocolysis) DA constriction model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological knockout approach mimicking genetic KO, in vivo functional readout, single lab\",\n      \"pmids\": [\"14607269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ET(A) receptor mediates ET-1-potentiated insulin secretion in mouse pancreatic islets via PKC: ET(A) antagonist BQ123 blocked ET-1-stimulated insulin secretion at 1–10,000 nM; PKC inhibitor calphostin C and PKC downregulation abolished the insulinotropic effect of ET-1; ET(B) agonist BQ3020 had no effect.\",\n      \"method\": \"Isolated mouse islets of Langerhans; insulin secretion assay; selective ET(A) antagonist BQ123; ET(B) agonist BQ3020; PKC activator TPA; PKC inhibitor calphostin C; PKC downregulation by TPA pretreatment; Wortmannin (PI3K inhibitor)\",\n      \"journal\": \"Metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro functional assay with multiple pharmacological tools dissecting receptor subtype and signaling pathway, single lab\",\n      \"pmids\": [\"10690956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EDNRA promotes colorectal cancer (CRC) progression through a positive feedback loop with EDN1 mediated by STAT3: EDNRA knockdown suppressed STAT3 phosphorylation; STAT3 silencing decreased EDN1 and EDNRA expression; STAT3 directly bound EDNRA and EDN1 promoters (shown by ChIP and promoter assays); EDNRA overexpression promoted cell proliferation and migration.\",\n      \"method\": \"CRC cell lines; phosphokinase array; EDNRA knockdown/overexpression; STAT3 silencing; ChIP assay; promoter assay; proliferation and migration assays; macitentan (EDNRA antagonist) treatment\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (phosphokinase array, ChIP, promoter assay, functional assays), mechanistic loop defined, single lab\",\n      \"pmids\": [\"36453252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ET-1 induces contraction of female rat internal pudendal and clitoral arteries through the ET(A) receptor and Rho-kinase activation: ET(A)R antagonist atrasentan reduced ET-1-induced contraction and shifted pD2; Rho-kinase inhibitor Y-27632 also shifted ET-1 pD2; ET(A)R, RhoA, and Rho-kinase proteins were detected by Western blot in IPA.\",\n      \"method\": \"Isolated artery myograph experiments; selective ET(A)R antagonist atrasentan; Rho-kinase inhibitor Y-27632; Western blot and real-time PCR for ET(A)R, ET(B)R, RhoA, Rho-kinase in rat IPA\",\n      \"journal\": \"The journal of sexual medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ex vivo contractility assay with pharmacological dissection and molecular confirmation, single lab\",\n      \"pmids\": [\"20412427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Autoantibodies targeting ETAR (ET(A) receptor) in scleroderma renal crisis activate the MAPK pathway and downstream Ets-1 transcription factor in endothelial cells, inducing endothelial proliferation and tissue factor (TF) expression; ETAR inhibitors/shRNA abrogated these effects, confirming ETAR-dependent signaling.\",\n      \"method\": \"Patient-derived IgG from scleroderma renal crisis applied to endothelial cells; MAPK pathway activation assay; Ets-1 immunostaining; TF promoter assay; ETAR inhibitors and shRNA knockdown; endothelial cell proliferation assay; TF inhibition\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (pathway activation, ChIP-like promoter binding, shRNA, pharmacological inhibition, functional proliferation assay), single lab\",\n      \"pmids\": [\"35008670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EDNRA Ser420Thr mutation was identified as a causative mutation for familial ACTH-independent macronodular adrenal hyperplasia (AIMAH) by whole exome sequencing and disease network analysis in an affected pedigree.\",\n      \"method\": \"Whole exome sequencing of familial AIMAH pedigree; variant prioritization via disease network analysis; adrenalectomy tissue samples\",\n      \"journal\": \"Familial cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic identification by sequencing without functional validation of the mutation's mechanism, single family\",\n      \"pmids\": [\"23754170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"ET(A) receptor activation in rat cortical astrocytes mediates phospholipase D (PLD) activation: approximately 20% of ET-1-induced PLD activation was mediated by ET(A) receptors (remaining ~80% by ET(B) receptors); after ET(B) receptor desensitization, the remaining ET-1-induced PLD response was fully blocked by BQ-123 (ET(A) antagonist).\",\n      \"method\": \"Primary rat cortical astrocyte cultures; [32P]phosphatidylbutanol formation assay for PLD activity; selective ET(A) antagonist BQ-123 and ET(B) antagonist BQ-788; receptor desensitization paradigms\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical assay with quantitative pharmacological dissection of receptor contribution, desensitization controls, single lab\",\n      \"pmids\": [\"9756390\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EDNRA (ET(A) receptor) is a G protein-coupled receptor (primarily Gαq) expressed on vascular smooth muscle, cardiac, renal, and neuronal cells that mediates vasoconstriction, vascular and cardiac hypertrophy, fibrosis, and cell proliferation upon binding endothelin-1 or endothelin-2; mechanistically, ET(A) receptor activates Gαq/IP3-mediated intracellular Ca2+ release and PKC, inhibits K_ATP and Kv channels (promoting vasoconstriction), activates ERK1/2 (driving fibroblast proliferation and myofibroblast differentiation), suppresses ENaC-mediated renal sodium reabsorption, sensitizes TRPA1 channels via PKA (contributing to pain signaling), promotes MMP activation and TGF-β1-dependent collagen synthesis in the heart, and mediates ductus arteriosus closure postnatally; in cancer, ET(A) receptor activates PI3K/Akt (promoting cell survival) and forms a positive feedback loop with STAT3/EDN1 to drive proliferation and migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EDNRA encodes the endothelin type A receptor (ET(A)), a Gαq-coupled G protein-coupled receptor that, upon binding endothelin-1 (or endothelin-2), drives vasoconstriction, vascular and cardiac structural remodeling, fibrosis, cell proliferation, and survival across vascular, cardiac, renal, neuronal, endocrine, and tumor contexts [#3, #19]. The proximal signaling output is dissected most fully in human cardiac fibroblasts, where ligand-activated ET(A) signals through Gαq and ERK1/2 to drive proliferation and myofibroblast differentiation with α-SMA and collagen I synthesis [#19]; in neuroblastoma cells ET(A) couples to both PTX-insensitive IP3-mediated Ca2+ mobilization from intracellular stores and a PTX-sensitive Ca2+ influx and inhibition of cAMP formation [#3]. Through these cascades ET(A) inhibits ion channels — L-type voltage-sensitive Ca2+ channels in cerebellar granule neurons [#4], K_ATP channels underlying hypoxic pulmonary vasoconstriction [#2], and voltage-gated Kv channels in pulmonary artery smooth muscle [#9] — and engages PKC- and Rho-kinase-dependent contraction [#24, #26]. In the heart, ET(A) mediates hypertrophy and remodeling: cardiac-specific ET(A) knockout protects against cold-stress hypertrophy, contractile dysfunction, ROS generation and apoptosis, abolishing downstream GSK3β/GATA4/CREB activation [#14], and ET(A) drives post-infarct MMP activation and TGF-β1-dependent collagen deposition [#5, #6]. In the kidney, ET(A) specifically regulates the ENaC-dependent component of collecting duct sodium transport and modulates NOS1 expression [#17, #12]. In cancer, ET(A) confers PI3K/Akt-dependent apoptosis resistance [#10] and forms a STAT3-EDN1 positive feedback loop promoting colorectal cancer proliferation and migration [#25]. An activating EDNRA Ser420Thr mutation segregates with familial ACTH-independent macronodular adrenal hyperplasia [#28]. ET(A) localizes predominantly to the plasma membrane and desensitizes more slowly than ET(B), with the two receptors functionally cross-regulating one another [#11, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that ET(A) is the receptor through which endothelin-1 drives vascular hypertrophy and cardiomyocyte growth, linking the receptor to structural remodeling rather than acute tone alone.\",\n      \"evidence\": \"Selective ET(A) antagonism (LU135252) in an angiotensin II rat model with vascular morphometry, plus pharmacological dissection in isolated rabbit ventricular cardiomyocytes\",\n      \"pmids\": [\"9315552\", \"9125673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve the intracellular signaling cascade linking ET(A) to growth\", \"Cardiomyocyte study implicated both ET(A) and ET(B), leaving relative contributions unsettled\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the proximal G protein coupling of ET(A), showing dual Ca2+-handling mechanisms and cAMP inhibition, and showed receptor-specific modulation of neuronal Ca2+ channels.\",\n      \"evidence\": \"Multimodal in vitro dissection (Ca2+ imaging, IP accumulation, cAMP, binding, PTX) in ET(A)-only SK-N-MC cells and patch-clamp of cerebellar granule neurons\",\n      \"pmids\": [\"9863648\", \"9716711\", \"9453352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the specific Gαq vs Gαi isoforms in native tissue\", \"PLD and other effector arms only partially mapped\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Connected ET(A) signaling to K_ATP channel inhibition as the mechanism of hypoxic pulmonary vasoconstriction and to PKC-dependent endocrine secretion, broadening the receptor's effector repertoire.\",\n      \"evidence\": \"Pharmacological epistasis with glibenclamide rescue in perfused rat lungs; PKC inhibitor experiments in mouse pancreatic islets; in vivo neonatal ductus arteriosus closure model\",\n      \"pmids\": [\"10710514\", \"10690956\", \"14607269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between ET(A) and channel gating not established\", \"Developmental ductus role inferred pharmacologically rather than by tissue-specific genetics\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Established ET(A) as a driver of cardiac and vascular pathological remodeling through MMP activation and TGF-β1-dependent fibrosis, and confirmed its contribution to human coronary vasoconstrictor tone.\",\n      \"evidence\": \"Selective antagonists (sitaxsentan, A-127722, BQ-123) in rat post-MI and DOCA-salt models with zymography, histology and TGF-β1 quantification; intracoronary BQ-123 infusion in patients\",\n      \"pmids\": [\"11179039\", \"11208696\", \"11717152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type origin of fibrotic signaling not resolved in vivo\", \"Did not define the kinase cascade upstream of MMP/TGF-β1\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed ET(A) couples to PI3K/Akt survival signaling and characterized its plasma membrane localization and slow desensitization relative to ET(B), establishing receptor-level regulatory distinctions.\",\n      \"evidence\": \"PI3K/Akt pathway inhibition with paclitaxel apoptosis assays in RCC lines; immunocytochemistry and Ca2+ desensitization kinetics in transfected HEK293 cells\",\n      \"pmids\": [\"16581180\", \"16740992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Desensitization machinery (GRK/arrestin) not identified\", \"Survival signaling characterized only in cancer cell lines\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined ET(A)'s renal role as the specific regulator of ENaC-dependent collecting duct sodium transport and reported an activating EDNRA mutation in a Mendelian adrenal disorder.\",\n      \"evidence\": \"Microperfusion of isolated mouse cortical collecting ducts with benzamil and subtype-selective antagonists; whole exome sequencing of a familial AIMAH pedigree\",\n      \"pmids\": [\"23698114\", \"23754170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"EDNRA Ser420Thr was identified by sequencing without functional validation\", \"Signaling linking ET(A) to ENaC regulation not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed functional cross-talk in which ET(A) blockade unmasks ET(B) overstimulation, increasing vascular permeability and fluid retention, clarifying receptor interplay in vivo.\",\n      \"evidence\": \"Selective vs dual antagonists, Brattleboro rats, and isolated vessel permeability experiments in rats\",\n      \"pmids\": [\"28223322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the ET(A)/ET(B) cross-regulation not defined\", \"Human relevance of the permeability effect not directly tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a discrete ET(A)-PKA-TRPA1 axis as a peripheral pain-sensitization mechanism, extending ET(A) signaling into nociception.\",\n      \"evidence\": \"Ca2+ imaging, patch clamp, ETAR/TRPA1 co-localization in DRG neurons, and behavioral pharmacology in mice\",\n      \"pmids\": [\"30990108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PKA acts directly on TRPA1 vs intermediate substrates not resolved\", \"Contribution to clinical pain states not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Fully dissected the Gαq/ERK1/2 pathway driving ET(A)-dependent cardiac fibroblast proliferation and myofibroblast differentiation, and defined a STAT3/EDN1 feedback loop in colorectal cancer.\",\n      \"evidence\": \"Selective G-protein and ERK1/2 inhibitors with proliferation and marker assays in human cardiac fibroblasts; phosphokinase array, ChIP and promoter assays in CRC cell lines\",\n      \"pmids\": [\"36901906\", \"36453252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo validation of the Gαq/ERK1/2 fibroblast axis pending\", \"STAT3/EDN1 loop demonstrated in cell lines only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EDNRA selectively partitions among its multiple downstream effectors (Gαq/IP3, PKC, Rho-kinase, PI3K/Akt, ERK1/2, channel modulation) in a tissue- and ligand-specific manner remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ligand- or context-dependent effector bias\", \"Determinants of ET(A) vs ET(B) coupling switching during disease not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 19]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 4, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 19]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [7, 26]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EDN1\", \"STAT3\", \"TRPA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}