{"gene":"EDNRB","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1991,"finding":"Human EDNRB cDNA was cloned and functionally expressed in COS cells, demonstrating that the receptor binds endothelin isopeptides (ET-1 and ET-3) with approximately equal potency and couples to intracellular Ca2+ transients ([Ca2+]i increases), establishing its non-isopeptide-selective pharmacology.","method":"cDNA cloning, radioligand binding (125I-ET-1 displacement), Ca2+ imaging in transfected COS cells","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct reconstitution of receptor function via cDNA transfection with binding and signaling assays; foundational cloning paper","pmids":["1713452"],"is_preprint":false},{"year":1992,"finding":"In vivo pharmacological activation of EDNRB with the selective agonist sarafotoxin S6c produces both a transient vasodepressor (endothelium-dependent vasodilation) and a subsequent sustained pressor response with renal and mesenteric vasoconstriction, demonstrating that EDNRB mediates both vasodilation and vasoconstriction in vivo.","method":"In vivo pharmacology in rats using selective ETB agonist sarafotoxin S6c; blood pressure and vascular resistance measurements","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct in vivo pharmacological dissection with selective agonist, replicated across multiple vascular beds","pmids":["1323294"],"is_preprint":false},{"year":1993,"finding":"EDNRB protein localizes to endothelial cells in multiple tissues (kidney, adrenal gland, lung, cerebellum, pituitary gland) as determined by immunohistochemistry using a receptor-specific antiserum that immunoprecipitates only ETB and not ETA; tissue-specific ETB:ETA ratios were quantified (e.g., lung ~70% ETB, testis <2% ETB).","method":"Immunohistochemistry, Western blot, and immunoprecipitation with subtype-specific antiserum","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunoprecipitation and immunohistochemistry with specific antiserum, single lab","pmids":["8476120"],"is_preprint":false},{"year":1994,"finding":"Both ETA and ETB receptors mediate contraction in human vascular smooth muscle cells; EDNRB-specific stimulation with sarafotoxin S6c induces contraction in ETA-blocked vessels, and ETB mRNA was detected by Northern blot in smooth muscle cells, establishing that smooth muscle ETB receptors are functionally contractile.","method":"Pharmacological antagonism (FR139317, BQ-123, bosentan), sarafotoxin S6c agonism, ETB receptor downregulation by prolonged sarafotoxin S6c preincubation, Northern blot for ETB mRNA","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal pharmacological methods in human tissue with ETB downregulation controls; replicated across multiple vessel types","pmids":["8124808"],"is_preprint":false},{"year":1994,"finding":"Both ETA and ETB receptors couple to the MAPK cascade (activation of p42 MAPK and MAPKK) and stimulate cell proliferation ([3H]thymidine uptake), as demonstrated in CHO cells transfected with either human ETA or ETB cDNA; ET isopeptide potency differences reflect receptor binding affinities.","method":"cDNA transfection of CHO cells, MAPK activity assays, [3H]thymidine incorporation","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct reconstitution in transfected cells with multiple signaling readouts; clean receptor-specific comparison","pmids":["7943276"],"is_preprint":false},{"year":1996,"finding":"ETB receptor activation (by ET-1 in OKPETB6 cells overexpressing EDNRB) stimulates NHE3 (Na+/H+ exchanger isoform 3) activity via tyrosine kinase pathways; ET-1 induces tyrosine phosphorylation of paxillin (68 kDa) and p125FAK via ETB, and this focal adhesion kinase pathway is not required for antiporter activation, whereas a membrane-associated 210 kDa phosphoprotein may mediate 50% of the NHE3 activation.","method":"Na+/H+ antiporter activity assays, immunoprecipitation, tyrosine phosphorylation assays, cytochalasin D disruption of focal adhesions in OKP cells overexpressing ETB","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (antiporter activity, immunoprecipitation, pharmacological dissection) in a well-defined cell system","pmids":["8843705"],"is_preprint":false},{"year":1999,"finding":"EDNRB activation by ET-1 induces NHE3 phosphorylation on multiple threonine and serine residues in OKP cells expressing ETB receptors (but not ETA receptors); phosphorylation is maximal at 15–30 min with 1 nM ET-1 and correlates temporally and in concentration dependence with NHE3 activation, suggesting phosphorylation mediates ETB-stimulated NHE3 activity.","method":"Na+/H+ antiporter activity assays, immunoprecipitation, SDS-PAGE mobility shift, alkaline phosphatase treatment, phosphoamino acid analysis in OKP cells with ETB or ETA receptors","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in receptor-transfected cells with biochemical validation of phosphorylation; multiple orthogonal methods","pmids":["10199826"],"is_preprint":false},{"year":1999,"finding":"Genetic and pharmacological disruption of EDNRB in mice elevates arterial blood pressure by ~20 mmHg; this depressor effect of endogenous ET acting through ETB is mediated in part by tonic prostaglandin production (attenuated by indomethacin but not by L-NMMA), not through respiratory control or ET clearance.","method":"ETB knockout/hypomorphic mouse model (ETB-/s vs ETB+/s), selective ETB antagonist BQ-788, selective ETA antagonist BQ-123, indomethacin and L-NMMA pharmacology, blood pressure telemetry","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function combined with pharmacological dissection of signaling mediators; multiple mechanistic controls","pmids":["10198387"],"is_preprint":false},{"year":2001,"finding":"The EDNRB gene 5' CpG island undergoes tissue-specific methylation that silences transcription; low methylation in a small region within the 5' region correlates with expression of the 5'-most transcript, and treatment with 5-aza-2'-deoxycytidine reactivates all four EDNRB transcripts, establishing promoter methylation as a regulatory mechanism.","method":"Bisulfite sequencing of 11 individual CpG sites, methylation-sensitive restriction fingerprinting, 5-aza-2'-deoxycytidine demethylation, RT-PCR for transcript expression","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct bisulfite sequencing plus pharmacological demethylation with transcript rescue; multiple orthogonal methods","pmids":["11309363"],"is_preprint":false},{"year":2003,"finding":"EDNRB activation specifically enhances RET signaling-induced proliferation of uncommitted ENS progenitors; EDNRB and RET signaling have opposing (antagonistic) roles in ENS progenitor migration; protein kinase A (PKA) is a key molecular integrator of EDNRB and RET pathway crosstalk during enteric nervous system development.","method":"Primary ENS progenitor culture assays with selective receptor agonists/antagonists, PKA inhibitor/activator pharmacology, proliferation and migration assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct cellular assays with pharmacological dissection of both pathways and PKA mechanism; multiple readouts","pmids":["14659090"],"is_preprint":false},{"year":2003,"finding":"Genetic titration of Ednrb in Ret kinase-null heterozygous mice demonstrates tissue-specific epistasis: EDNRB-RET interaction is restricted to the enteric nervous system and does not affect renal, melanocyte, or retinal choroid development; the degree of Ednrb dosage determines both penetrance and sex bias of aganglionosis.","method":"Two-locus noncomplementation assay in mice, allelic series at Ednrb in Ret+/- background, phenotypic analysis of enteric, renal, and coat color phenotypes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in multiple allelic combinations in mice with tissue-specific phenotypic readouts","pmids":["12574515"],"is_preprint":false},{"year":2008,"finding":"Renal medullary EDNRB stimulation (by sarafotoxin S6c infusion) induces diuresis and natriuresis through a NOS1 → cGMP → PKG signaling cascade; S6c-induced increases in urine flow, sodium excretion, and medullary cGMP were absent in ETB receptor-deficient rats and were abolished by selective NOS1 inhibitor or PKG inhibitor.","method":"In vivo renal medullary infusion in anesthetized rats, ETB-deficient rat model, selective NOS1 inhibitor (N(G)-propyl-L-arginine), PKG inhibitor, cGMP measurement, urine flow and sodium excretion","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function combined with selective pharmacological pathway inhibition; multiple mechanistic steps confirmed","pmids":["18305094"],"is_preprint":false},{"year":2008,"finding":"ET-1 impairs alveolar fluid reabsorption via endothelial EDNRB: ETB (not ETA) blockade prevents ET-1-induced decrease in alveolar fluid reabsorption; ET-1 acts on endothelial EDNRB to produce NO (cGMP-independent mechanism) that in turn decreases Na,K-ATPase activity and plasma membrane abundance in alveolar epithelial cells; transgenic rats deficient in pulmonary vascular ETB receptors are protected.","method":"Isolated perfused rat lung, ETB-deficient transgenic rats, endothelial-epithelial cell co-culture, ETB/ETA antagonist pharmacology, Na,K-ATPase activity assay, NO synthase inhibitor L-NAME","journal":"American journal of respiratory and critical care medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function plus pharmacological dissection plus mechanistic cell biology across multiple experimental systems","pmids":["18948426"],"is_preprint":false},{"year":2010,"finding":"Endothelial cell-specific EDNRB is the primary site responsible for clearance of circulating ET-1; endothelial-specific ETB knockout mice show impaired 125I-ET-1 clearance and elevated plasma ET-1, while ETB binding is selectively decreased in EC-rich tissues (lung, liver, kidney).","method":"Endothelial cell-specific Cre-lox ETB knockout mice, 125I-ET-1 clearance assay, autoradiography, immunocytochemistry, RT-PCR, selective ETB antagonist A192621","journal":"Canadian journal of physiology and pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic knockout with direct clearance assay and pharmacological confirmation","pmids":["20628430"],"is_preprint":false},{"year":2015,"finding":"After status epilepticus, EDNRB activation drives vasogenic edema by stimulating endothelial eNOS, increasing MMP-9 activity, and degrading the tight junction protein ZO-1 in endothelial cells; ETB antagonist BQ788 attenuates SE-induced vasogenic edema by blocking eNOS-MMP-9-ZO-1 degradation.","method":"In vivo rat SE model, ETB antagonist BQ788, immunohistochemistry/immunofluorescence for tight junction proteins, MMP-9 activity assay, eNOS activation assay","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological loss-of-function with defined molecular pathway; single lab","pmids":["26232046"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of human EDNRB in ligand-free and ET-1-bound forms reveals that transmembrane helices 1, 2, 6, and 7 move to envelop the entire ET-1 peptide in a virtually irreversible manner; agonist-induced conformational changes propagate to the cytoplasmic G-protein coupling interface and induce flexibility in TM6; mutation analysis defines the mechanism for ET-1 versus ET-3 isopeptide selectivity.","method":"X-ray crystallography, site-directed mutagenesis, functional Ca2+ assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with mutagenesis validation; multiple orthogonal methods in a single rigorous study","pmids":["27595334"],"is_preprint":false},{"year":2016,"finding":"EDNRB signaling in melanocyte stem cells promotes their proliferation and differentiation to regenerate hair and epidermal melanocytes; this effect requires active Wnt signaling initiated by Wnt ligand secretion from the hair follicle epithelial niche, and Wnt-dependent EDNRB signaling can rescue defects caused by Mc1R loss.","method":"Genetic loss-of-function (EdnrB knockout in melanocyte stem cells), Wnt signaling inhibition/activation, in vivo melanocyte regeneration assays, Mc1R mutant rescue","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic knockout with pathway epistasis (Wnt requirement) and functional rescue","pmids":["27134165"],"is_preprint":false},{"year":2017,"finding":"Epilation induces endogenous EDN3 upregulation in the dermal papilla, secondary hair germ cells, and epidermis; genetic and pharmacological disruption of EDNRB blocks melanocyte stem cell activation, follicular and epidermal melanocyte regeneration, and skin/hair hyperpigmentation after epilation.","method":"In vivo mouse epilation model, EDNRB genetic disruption (conditional knockout), pharmacological EDNRB blockade, immunofluorescence for melanocyte markers","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function plus pharmacological confirmation with defined upstream ligand (EDN3) and functional readouts","pmids":["28779103"],"is_preprint":false},{"year":2017,"finding":"EDNRB heterozygous missense mutations cause Waardenburg syndrome type II (pigmentation/hearing loss without Hirschsprung disease) with dominant incomplete penetrance; cellular studies showed that each of six identified mutations impairs subcellular localization of EDNRB or induces defective downstream signaling.","method":"Exome sequencing, family segregation analysis, cellular localization studies (immunofluorescence), downstream signaling assays in transfected cells","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cellular studies of subcellular localization and signaling for each mutation; single lab","pmids":["28236341"],"is_preprint":false},{"year":2017,"finding":"EDN3-mediated EDNRB signaling prevents premature neuronal differentiation of enteric nervous system progenitor cells; this requires two copies of Zeb2 (ZEB2). SOX10 and ZEB2 directly activate the EDNRB promoter (confirmed by chromatin immunoprecipitation and transactivation assays), and overexpression of EDNRB in Zeb2-heterozygous EPCs restores EDN3-mediated inhibition of differentiation.","method":"Enteric progenitor cell cultures, Zeb2 and Edn3 mutant mouse crosses, chromatin immunoprecipitation, transactivation assays, retroviral EDNRB rescue, immunocytochemistry","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP + transactivation assays + genetic rescue across multiple experimental systems; multiple orthogonal methods","pmids":["28063956"],"is_preprint":false},{"year":2018,"finding":"Crystal structures of human EDNRB bound to ET-3 and the partial agonist IRL1620 reveal that disruption of water-mediated interactions between W6.48 and D2.50 is critical for full receptor activation; IRL1620 partially preserves these hydrogen-bonding interactions, explaining its partial agonism confirmed by functional analysis.","method":"X-ray crystallography of ETB-ET3 and ETB-IRL1620 complexes, site-directed mutagenesis, functional Ca2+ signaling assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with mutagenesis and functional validation; mechanistic explanation of partial agonism","pmids":["30413709"],"is_preprint":false},{"year":2019,"finding":"EDNRB transcription in the enteric nervous system is directly regulated by transcription factors GATA2, SOX10, and NKX2.5; RET and EDNRB share GATA2 and SOX10 as regulators, and these TFs are in turn controlled by EDNRB and RET in a dose-dependent feedback manner, explaining RET-EDNRB epistasis in Hirschsprung disease.","method":"Human and mouse cellular models, ChIP assays, reporter gene assays, animal models of EDNRB and RET expression","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus reporter assays plus genetic animal models; multiple orthogonal methods across human and mouse systems","pmids":["31313802"],"is_preprint":false},{"year":2009,"finding":"D3 dopamine receptors physically interact with EDNRB (co-immunoprecipitation) in renal proximal tubule cells; D3 receptor activation increases ETB receptor expression (calcium-dependent, blocked by nicardipine) in WKY rats and augments ETB-mediated inhibition of Na+/K+-ATPase activity; this D3-ETB interaction is impaired in spontaneously hypertensive rats.","method":"Co-immunoprecipitation, immunoblotting, RT-PCR, Na+/K+-ATPase activity assay, selective agonist/antagonist pharmacology","journal":"American journal of hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-immunoprecipitation plus functional assays; single lab, two orthogonal methods","pmids":["19390510"],"is_preprint":false},{"year":2008,"finding":"ETB receptor activation mediates apoptosis of retinal ganglion cells (RGC-5 cells) via cytochrome c release from mitochondria and JNK phosphorylation; ET-1-induced apoptosis was markedly attenuated in ETB receptor-deficient rats and by ETB antagonist BQ788 in cultured cells.","method":"Flow cytometry, cytochrome c release assay, JNK phosphorylation assay, ETB-deficient rat model, BQ788 pharmacology","journal":"Canadian journal of physiology and pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function (ETB-deficient rats) plus pharmacological blockade plus mechanistic pathway assays; single lab","pmids":["18516102"],"is_preprint":false},{"year":1997,"finding":"A critical proline residue in the fifth transmembrane domain of EDNRB is required for function in vivo (Ednrb27Pub allele); loss of authentic Ednrb mRNA (Ednrb3Chlo allele, gross genomic deletion) or reduced mRNA level (Ednrb17FrS) causes juvenile lethality and pigmentation defects, demonstrating that EDNRB expression level is dosage-sensitive for melanocyte development.","method":"Molecular characterization of four ENU/radiation-induced mouse Ednrb alleles by sequencing, mRNA analysis (Northern blot/RT-PCR), and phenotypic analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent alleles with molecular characterization and in vivo phenotypic validation; establishes structure-function at specific domain","pmids":["9371807"],"is_preprint":false},{"year":2018,"finding":"miR-124-3p directly targets EDNRB (confirmed by dual-luciferase reporter assay); miR-124-3p suppresses EDNRB expression and thereby inhibits bladder cancer cell proliferation and induces apoptosis; EDNRB siRNA phenocopies miR-124-3p mimic effects.","method":"Dual-luciferase reporter assay, qRT-PCR, Western blot, siRNA knockdown, cell proliferation (MTS/colony assay), flow cytometry apoptosis assay, nude mouse tumorigenicity assay","journal":"Archives of medical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter plus knockdown rescue with functional readouts; single lab","pmids":["31572460"],"is_preprint":false},{"year":2018,"finding":"Homocysteine upregulates EDNRB in vascular smooth muscle cells by inhibiting autophagy via the AMPK/mTOR signaling pathway; AMPK activator (AICAR) or mTOR inhibitor (rapamycin) reverses Hcy-induced ETB receptor upregulation and contractile responses, while mTOR activator (MHY1485) restores the effect.","method":"Rat superior mesenteric artery myograph, Western blot, immunofluorescence for LC3B (autophagy marker), AICAR/rapamycin/MHY1485 pharmacology","journal":"Microvascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional vascular assay plus molecular pathway analysis with pharmacological pathway rescue; single lab","pmids":["29601873"],"is_preprint":false}],"current_model":"EDNRB is a class A GPCR that, upon binding endothelins (ET-1, ET-2, ET-3 with equal potency), undergoes a ligand-induced conformational change in which TM helices 1, 2, 6, and 7 envelop the peptide—disrupting a W6.48–D2.50 water-mediated interaction to enable full G-protein coupling—and signals through Ca2+ mobilization, MAPK activation, tyrosine kinase pathways (including FAK/paxillin), PKA, and NOS1/cGMP/PKG; endothelial EDNRB is the primary site for ET-1 clearance from the circulation and mediates vasodilation (via NO/prostaglandins), while smooth muscle EDNRB mediates vasoconstriction; in the kidney it promotes natriuresis via NOS1-cGMP-PKG; in ENS and melanocyte development, EDNRB cooperates with RET (integrated through a shared GATA2/SOX10 gene regulatory network) and with Wnt signaling to control neural crest progenitor proliferation, migration, and differentiation timing, with EDNRB expression itself directly transcriptionally regulated by SOX10, ZEB2, GATA2, and NKX2.5; loss-of-function mutations cause Hirschsprung disease and Waardenburg syndrome through failure of enteric neuron and melanocyte colonization, while promoter CpG hypermethylation silences EDNRB in multiple cancers."},"narrative":{"mechanistic_narrative":"EDNRB is a class A G-protein-coupled receptor that binds the endothelin isopeptides ET-1 and ET-3 with approximately equal potency and couples to intracellular Ca2+ mobilization, defining its non-isopeptide-selective pharmacology [PMID:1713452]. Crystal structures of ligand-free and ET-1-, ET-3-, and partial-agonist-bound receptor show that transmembrane helices 1, 2, 6, and 7 close around the peptide in an essentially irreversible manner, and that disruption of a water-mediated W6.48–D2.50 interaction propagates conformational change to the cytoplasmic G-protein interface to drive full activation [PMID:27595334, PMID:30413709]. Downstream of receptor engagement, EDNRB activates the MAPK cascade and proliferation [PMID:7943276], tyrosine-kinase pathways including FAK and paxillin that regulate the Na+/H+ exchanger NHE3 [PMID:8843705, PMID:10199826], and NOS/cGMP/PKG signaling [PMID:18305094]. The receptor exerts opposing vascular actions in vivo, mediating both endothelium-dependent vasodilation and sustained vasoconstriction [PMID:1323294, PMID:8124808]. Endothelial EDNRB is the primary clearance site for circulating ET-1 [PMID:20628430] and drives prostaglandin- and NO-dependent depressor tone, vasogenic edema through eNOS–MMP-9–ZO-1 degradation, and modulation of alveolar fluid reabsorption [PMID:10198387, PMID:18948426, PMID:26232046], while renal medullary EDNRB promotes diuresis and natriuresis via a NOS1→cGMP→PKG cascade [PMID:18305094]. In neural crest development EDNRB controls enteric progenitor proliferation, migration, and differentiation timing, integrating with RET signaling through PKA and a shared GATA2/SOX10 transcriptional network, with its own expression directly activated by SOX10, ZEB2, GATA2, and NKX2.5 [PMID:14659090, PMID:28063956, PMID:31313802], and it cooperates with Wnt signaling to drive melanocyte stem cell activation and regeneration [PMID:27134165, PMID:28779103]. Loss-of-function and dosage-sensitive mutations of EDNRB cause Hirschsprung disease and Waardenburg syndrome type II through failed enteric neuron and melanocyte colonization [PMID:28236341, PMID:9371807], and promoter CpG-island hypermethylation silences EDNRB transcription [PMID:11309363].","teleology":[{"year":1991,"claim":"Established that EDNRB is a functional endothelin receptor with non-selective isopeptide pharmacology, distinguishing it from the ETA subtype and defining its core signaling output.","evidence":"cDNA cloning and expression in COS cells with radioligand binding and Ca2+ imaging","pmids":["1713452"],"confidence":"High","gaps":["Did not resolve the structural basis of ligand binding","G-protein coupling specificity not defined"]},{"year":1992,"claim":"Showed that a single EDNRB-selective agonist produces both vasodilation and vasoconstriction in vivo, revealing dual and opposing vascular roles for one receptor.","evidence":"In vivo rat pharmacology with selective ETB agonist sarafotoxin S6c and hemodynamic measurements","pmids":["1323294"],"confidence":"High","gaps":["Cell types responsible for each response not distinguished","Downstream signaling mediators undefined"]},{"year":1993,"claim":"Localized EDNRB protein predominantly to endothelial cells across tissues and quantified tissue-specific ETB:ETA ratios, framing where the receptor acts.","evidence":"Immunohistochemistry, Western blot, and immunoprecipitation with subtype-specific antiserum","pmids":["8476120"],"confidence":"Medium","gaps":["Single-lab antiserum-based localization","Non-endothelial expression sites not fully mapped"]},{"year":1994,"claim":"Defined intracellular signaling outputs by showing EDNRB couples to the MAPK cascade and drives proliferation, and that smooth muscle ETB receptors are functionally contractile.","evidence":"CHO cDNA transfection with MAPK and thymidine incorporation assays; human vessel pharmacology with ETB downregulation controls and Northern blot","pmids":["7943276","8124808"],"confidence":"High","gaps":["Link between MAPK activation and physiological contraction not established","G-protein identity not defined"]},{"year":1999,"claim":"Connected EDNRB to renal ion transport by showing ETB-specific activation stimulates NHE3 via tyrosine-kinase pathways including FAK/paxillin and direct NHE3 phosphorylation.","evidence":"Na+/H+ antiporter activity, immunoprecipitation, phosphorylation and mobility-shift analyses in OKP cells expressing ETB vs ETA","pmids":["8843705","10199826"],"confidence":"High","gaps":["Identity of the 210 kDa phosphoprotein mediator unknown","Kinase acting directly on NHE3 not identified"]},{"year":1999,"claim":"Demonstrated in vivo that endogenous ETB tone lowers blood pressure largely through prostaglandin production, dissecting the depressor mechanism.","evidence":"ETB hypomorphic mice with selective antagonists, indomethacin and L-NMMA, and blood pressure telemetry","pmids":["10198387"],"confidence":"High","gaps":["Cellular source of prostaglandins not pinpointed","Relationship to ET clearance not resolved here"]},{"year":2003,"claim":"Revealed how EDNRB integrates with RET during enteric nervous system development, identifying PKA as the crosstalk node and demonstrating tissue-restricted genetic epistasis.","evidence":"Primary ENS progenitor assays with PKA pharmacology; two-locus noncomplementation and allelic-series genetics in Ret-null mice","pmids":["14659090","12574515"],"confidence":"High","gaps":["Molecular basis of opposing migration vs proliferation effects unresolved","Direct PKA substrates not identified"]},{"year":2008,"claim":"Defined organ-specific EDNRB signaling cascades: NOS1-cGMP-PKG-driven natriuresis in renal medulla, NO-dependent suppression of alveolar Na,K-ATPase, and a mitochondrial apoptotic pathway in retinal cells.","evidence":"In vivo renal infusion and lung perfusion in ETB-deficient rats with NOS/PKG inhibitors; flow cytometry and cytochrome c/JNK assays in RGC-5 cells","pmids":["18305094","18948426","18516102"],"confidence":"High","gaps":["Apoptosis pathway shown in a single lab","Cell-type specificity of NO source in lung not fully resolved"]},{"year":2010,"claim":"Established endothelial EDNRB as the principal clearance receptor for circulating ET-1 using cell-type-specific genetics.","evidence":"Endothelial-specific Cre-lox ETB knockout mice with 125I-ET-1 clearance, autoradiography, and selective antagonist","pmids":["20628430"],"confidence":"High","gaps":["Intracellular fate of internalized ET-1 not traced","Contribution to circulating ET-1 setpoint in disease undefined"]},{"year":2016,"claim":"Provided the structural mechanism of activation, showing TM1/2/6/7 envelopment of endothelin and propagation of conformational change to the G-protein interface.","evidence":"X-ray crystallography of ligand-free and ET-1-bound EDNRB with mutagenesis and Ca2+ assays","pmids":["27595334"],"confidence":"High","gaps":["No active-state complex with bound G protein","Dynamics of irreversible binding not captured"]},{"year":2016,"claim":"Showed EDNRB drives melanocyte stem cell proliferation and regeneration in a Wnt-dependent manner, placing it within a niche signaling network.","evidence":"Melanocyte-stem-cell-specific EdnrB knockout, Wnt modulation, and Mc1R mutant rescue in vivo","pmids":["27134165"],"confidence":"High","gaps":["Molecular point of Wnt-EDNRB convergence not defined","Downstream effectors in stem cells unidentified"]},{"year":2017,"claim":"Connected EDNRB to disease and transcriptional control: WS2-causing mutations impair localization/signaling, EDN3-EDNRB prevents premature ENS differentiation, and SOX10/ZEB2 directly activate the EDNRB promoter.","evidence":"Exome sequencing and cellular assays of WS2 mutations; epilation-induced EDN3 in vivo; ChIP, transactivation, and retroviral rescue in enteric progenitors","pmids":["28236341","28779103","28063956"],"confidence":"High","gaps":["WS2 functional studies from a single lab","How differentiation timing is mechanistically held in check unresolved"]},{"year":2019,"claim":"Mapped the transcriptional regulatory logic explaining RET-EDNRB epistasis, showing GATA2, SOX10, and NKX2.5 directly drive EDNRB in a dose-dependent feedback network shared with RET.","evidence":"ChIP and reporter assays in human and mouse cellular models with animal expression analyses","pmids":["31313802"],"confidence":"High","gaps":["Quantitative dynamics of the feedback loop undefined","Tissue specificity of NKX2.5 input not fully resolved"]},{"year":null,"claim":"How EDNRB's full active-state signaling complexes (G protein, arrestin) are organized, and how cell-type-specific transcriptional and post-transcriptional control (methylation, miRNA, autophagy) is integrated to set receptor abundance in disease, remains incompletely defined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No active-state G-protein-bound structure in the corpus","Integration of methylation, miR-124-3p, and AMPK/mTOR control into a single regulatory model not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,15]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,16,19]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[1,3,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,24]}],"complexes":[],"partners":["EDN1","EDN3","RET","DRD3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P24530","full_name":"Endothelin receptor type B","aliases":["Endothelin receptor non-selective type"],"length_aa":442,"mass_kda":49.6,"function":"Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P24530/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EDNRB","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EDNRB","total_profiled":1310},"omim":[{"mim_id":"617630","title":"G PROTEIN-COUPLED RECEPTOR 37-LIKE 1; GPR37L1","url":"https://www.omim.org/entry/617630"},{"mim_id":"613712","title":"HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 4; HSCR4","url":"https://www.omim.org/entry/613712"},{"mim_id":"613265","title":"WAARDENBURG SYNDROME, TYPE 4B; WS4B","url":"https://www.omim.org/entry/613265"},{"mim_id":"608729","title":"ANGIOTENSIN II RECEPTOR-ASSOCIATED PROTEIN; AGTRAP","url":"https://www.omim.org/entry/608729"},{"mim_id":"608462","title":"HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 8; HSCR8","url":"https://www.omim.org/entry/608462"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"placenta","ntpm":120.1}],"url":"https://www.proteinatlas.org/search/EDNRB"},"hgnc":{"alias_symbol":["ETB"],"prev_symbol":["HSCR2","HSCR"]},"alphafold":{"accession":"P24530","domains":[{"cath_id":"1.20.1070.10","chopping":"97-400","consensus_level":"high","plddt":88.77,"start":97,"end":400}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P24530","model_url":"https://alphafold.ebi.ac.uk/files/AF-P24530-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P24530-F1-predicted_aligned_error_v6.png","plddt_mean":75.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EDNRB","jax_strain_url":"https://www.jax.org/strain/search?query=EDNRB"},"sequence":{"accession":"P24530","fasta_url":"https://rest.uniprot.org/uniprotkb/P24530.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P24530/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P24530"}},"corpus_meta":[{"pmid":"8124808","id":"PMC_8124808","title":"Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels.","date":"1994","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/8124808","citation_count":473,"is_preprint":false},{"pmid":"1323294","id":"PMC_1323294","title":"The endothelin ETB receptor mediates both vasodilation and vasoconstriction in vivo.","date":"1992","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1323294","citation_count":395,"is_preprint":false},{"pmid":"1713452","id":"PMC_1713452","title":"Cloning and functional expression of human cDNA for the ETB endothelin receptor.","date":"1991","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1713452","citation_count":272,"is_preprint":false},{"pmid":"1315540","id":"PMC_1315540","title":"A potent and specific agonist, Suc-[Glu9,Ala11,15]-endothelin-1(8-21), IRL 1620, for the ETB receptor.","date":"1992","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1315540","citation_count":258,"is_preprint":false},{"pmid":"7634449","id":"PMC_7634449","title":"Endothelin ETA and ETB receptors cause vasoconstriction of human resistance and capacitance vessels in vivo.","date":"1995","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/7634449","citation_count":256,"is_preprint":false},{"pmid":"17002597","id":"PMC_17002597","title":"Contrasting actions of endothelin ET(A) and ET(B) receptors in cardiovascular disease.","date":"2007","source":"Annual review of pharmacology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/17002597","citation_count":243,"is_preprint":false},{"pmid":"14659090","id":"PMC_14659090","title":"Enteric nervous system progenitors are coordinately controlled by the G protein-coupled receptor EDNRB and the receptor tyrosine kinase RET.","date":"2003","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/14659090","citation_count":213,"is_preprint":false},{"pmid":"8852660","id":"PMC_8852660","title":"Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease.","date":"1996","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8852660","citation_count":174,"is_preprint":false},{"pmid":"10393673","id":"PMC_10393673","title":"Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETB receptor blockade.","date":"1999","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/10393673","citation_count":136,"is_preprint":false},{"pmid":"27595334","id":"PMC_27595334","title":"Activation mechanism of endothelin ETB receptor by endothelin-1.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/27595334","citation_count":128,"is_preprint":false},{"pmid":"12574515","id":"PMC_12574515","title":"Phenotype variation in two-locus mouse models of Hirschsprung disease: tissue-specific interaction between Ret and Ednrb.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12574515","citation_count":119,"is_preprint":false},{"pmid":"7521470","id":"PMC_7521470","title":"Endothelin ETA- and ETB-receptor-mediated vasoconstriction in rat pulmonary arteries and arterioles.","date":"1994","source":"Journal of cardiovascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/7521470","citation_count":112,"is_preprint":false},{"pmid":"16650841","id":"PMC_16650841","title":"Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte development.","date":"2006","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16650841","citation_count":105,"is_preprint":false},{"pmid":"15294878","id":"PMC_15294878","title":"Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis in the Sox10Dom mouse model of Hirschsprung disease.","date":"2004","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15294878","citation_count":93,"is_preprint":false},{"pmid":"11309363","id":"PMC_11309363","title":"The endothelin receptor B (EDNRB) promoter displays heterogeneous, site specific methylation patterns in normal and tumor cells.","date":"2001","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11309363","citation_count":88,"is_preprint":false},{"pmid":"11434563","id":"PMC_11434563","title":"EDNRB/EDN3 and Hirschsprung disease type II.","date":"2001","source":"Pigment cell research","url":"https://pubmed.ncbi.nlm.nih.gov/11434563","citation_count":80,"is_preprint":false},{"pmid":"20162572","id":"PMC_20162572","title":"KIF1A and EDNRB are differentially methylated in primary HNSCC and salivary rinses.","date":"2010","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20162572","citation_count":80,"is_preprint":false},{"pmid":"10199843","id":"PMC_10199843","title":"Expression of endothelin-1, ETA and ETB receptors, and ECE and distribution of endothelin-1 in failing rat heart.","date":"1999","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10199843","citation_count":80,"is_preprint":false},{"pmid":"16231007","id":"PMC_16231007","title":"ETA and ETB receptors differentially modulate afferent and efferent arteriolar responses to endothelin.","date":"2005","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16231007","citation_count":77,"is_preprint":false},{"pmid":"10199826","id":"PMC_10199826","title":"ETB receptor activation leads to activation and phosphorylation of NHE3.","date":"1999","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10199826","citation_count":77,"is_preprint":false},{"pmid":"23637120","id":"PMC_23637120","title":"EDNRB and DCC salivary rinse hypermethylation has a similar performance as expert clinical examination in discrimination of oral cancer/dysplasia versus benign lesions.","date":"2013","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/23637120","citation_count":76,"is_preprint":false},{"pmid":"16835394","id":"PMC_16835394","title":"Distribution of endothelin receptor subtypes ETA and ETB in the rat kidney.","date":"2006","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/16835394","citation_count":76,"is_preprint":false},{"pmid":"27134165","id":"PMC_27134165","title":"EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27134165","citation_count":72,"is_preprint":false},{"pmid":"16269442","id":"PMC_16269442","title":"Evaluation of the RET regulatory landscape reveals the biological relevance of a HSCR-implicated enhancer.","date":"2005","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16269442","citation_count":67,"is_preprint":false},{"pmid":"12623975","id":"PMC_12623975","title":"Gender differences in ET and NOS systems in ETB receptor-deficient rats: effect of a high salt diet.","date":"2002","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/12623975","citation_count":67,"is_preprint":false},{"pmid":"30413709","id":"PMC_30413709","title":"Crystal structures of human ETB receptor provide mechanistic insight into receptor activation and partial activation.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30413709","citation_count":65,"is_preprint":false},{"pmid":"10198387","id":"PMC_10198387","title":"Elevation of blood pressure by genetic and pharmacological disruption of the ETB receptor in mice.","date":"1999","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10198387","citation_count":65,"is_preprint":false},{"pmid":"18305094","id":"PMC_18305094","title":"Renal medullary ETB receptors produce diuresis and natriuresis via NOS1.","date":"2008","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18305094","citation_count":64,"is_preprint":false},{"pmid":"14600022","id":"PMC_14600022","title":"Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR).","date":"2003","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14600022","citation_count":63,"is_preprint":false},{"pmid":"30171849","id":"PMC_30171849","title":"News from the endothelin-3/EDNRB signaling pathway: Role during enteric nervous system development and involvement in neural crest-associated disorders.","date":"2018","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/30171849","citation_count":62,"is_preprint":false},{"pmid":"8476120","id":"PMC_8476120","title":"Immunochemical characterization and localization of endothelin ETB receptor.","date":"1993","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8476120","citation_count":56,"is_preprint":false},{"pmid":"11302967","id":"PMC_11302967","title":"Analysis of the RET, GDNF, EDN3, and EDNRB genes in patients with intestinal neuronal dysplasia and Hirschsprung disease.","date":"2001","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/11302967","citation_count":55,"is_preprint":false},{"pmid":"20628430","id":"PMC_20628430","title":"Endothelial cell-specific ETB receptor knockout: autoradiographic and histological characterisation and crucial role in the clearance of endothelin-1.","date":"2010","source":"Canadian journal of physiology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20628430","citation_count":55,"is_preprint":false},{"pmid":"17873013","id":"PMC_17873013","title":"Cerebrovascular ETB, 5-HT1B, and AT1 receptor upregulation correlates with reduction in regional CBF after subarachnoid hemorrhage.","date":"2007","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17873013","citation_count":55,"is_preprint":false},{"pmid":"18516102","id":"PMC_18516102","title":"Role of the ETB receptor in retinal ganglion cell death in glaucoma.","date":"2008","source":"Canadian journal of physiology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18516102","citation_count":54,"is_preprint":false},{"pmid":"11920632","id":"PMC_11920632","title":"Promoter hypermethylation of the EDNRB gene in nasopharyngeal carcinoma.","date":"2002","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/11920632","citation_count":54,"is_preprint":false},{"pmid":"8843705","id":"PMC_8843705","title":"Role of tyrosine kinase pathways in ETB receptor activation of NHE3.","date":"1996","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8843705","citation_count":54,"is_preprint":false},{"pmid":"24326135","id":"PMC_24326135","title":"Hypermethylation of EDNRB promoter contributes to the risk of colorectal cancer.","date":"2013","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24326135","citation_count":51,"is_preprint":false},{"pmid":"17091294","id":"PMC_17091294","title":"MEK1/2 inhibition attenuates vascular ETA and ETB receptor alterations after cerebral ischaemia.","date":"2006","source":"Experimental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/17091294","citation_count":50,"is_preprint":false},{"pmid":"26232046","id":"PMC_26232046","title":"ETB receptor-mediated MMP-9 activation induces vasogenic edema via ZO-1 protein degradation following status epilepticus.","date":"2015","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26232046","citation_count":49,"is_preprint":false},{"pmid":"21782343","id":"PMC_21782343","title":"Re-expression of the methylated EDNRB gene in oral squamous cell carcinoma attenuates cancer-induced pain.","date":"2011","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/21782343","citation_count":46,"is_preprint":false},{"pmid":"23360229","id":"PMC_23360229","title":"Altered neuronal density and neurotransmitter expression in the ganglionated region of Ednrb null mice: implications for Hirschsprung's disease.","date":"2013","source":"Neurogastroenterology and motility","url":"https://pubmed.ncbi.nlm.nih.gov/23360229","citation_count":46,"is_preprint":false},{"pmid":"20009762","id":"PMC_20009762","title":"New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease.","date":"2010","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20009762","citation_count":44,"is_preprint":false},{"pmid":"8951723","id":"PMC_8951723","title":"Localization of endothelin ETA and ETB receptor-mediated constriction in the renal microcirculation of rats.","date":"1996","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8951723","citation_count":44,"is_preprint":false},{"pmid":"22589734","id":"PMC_22589734","title":"Genome-wide copy number analysis uncovers a new HSCR gene: NRG3.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22589734","citation_count":43,"is_preprint":false},{"pmid":"28438762","id":"PMC_28438762","title":"ETB receptor contribution to vascular dysfunction in postmenopausal women.","date":"2017","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28438762","citation_count":43,"is_preprint":false},{"pmid":"20473317","id":"PMC_20473317","title":"Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations.","date":"2010","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20473317","citation_count":41,"is_preprint":false},{"pmid":"8991802","id":"PMC_8991802","title":"Functional role of endothelin ETA and ETB receptors in venous and arterial smooth muscle.","date":"1995","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/8991802","citation_count":41,"is_preprint":false},{"pmid":"15721614","id":"PMC_15721614","title":"Delphinidin-3-rutinoside relaxes the bovine ciliary smooth muscle through activation of ETB receptor and NO/cGMP pathway.","date":"2005","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/15721614","citation_count":39,"is_preprint":false},{"pmid":"16391877","id":"PMC_16391877","title":"Aberrant methylation of EDNRB and p16 genes in hepatocellular carcinoma (HCC) in Taiwan.","date":"2006","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/16391877","citation_count":39,"is_preprint":false},{"pmid":"31572460","id":"PMC_31572460","title":"The effect of miR-124-3p on cell proliferation and apoptosis in bladder cancer by targeting EDNRB.","date":"2018","source":"Archives of medical science : AMS","url":"https://pubmed.ncbi.nlm.nih.gov/31572460","citation_count":38,"is_preprint":false},{"pmid":"12070534","id":"PMC_12070534","title":"BQ-788, a selective endothelin ET(B) receptor antagonist.","date":"2002","source":"Cardiovascular drug reviews","url":"https://pubmed.ncbi.nlm.nih.gov/12070534","citation_count":38,"is_preprint":false},{"pmid":"7499084","id":"PMC_7499084","title":"ETB and epidermal growth factor receptor stimulation of wound closure in bovine corneal epithelial cells.","date":"1995","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/7499084","citation_count":38,"is_preprint":false},{"pmid":"7943276","id":"PMC_7943276","title":"Endothelins stimulate mitogen-activated protein kinase cascade through either ETA or ETB.","date":"1994","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/7943276","citation_count":37,"is_preprint":false},{"pmid":"18948426","id":"PMC_18948426","title":"Endothelin-1 impairs alveolar epithelial function via endothelial ETB receptor.","date":"2008","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18948426","citation_count":37,"is_preprint":false},{"pmid":"15243299","id":"PMC_15243299","title":"Roles of endothelin ETA and ETB receptors in the pathogenesis of monocrotaline-induced pulmonary hypertension.","date":"2004","source":"Journal of cardiovascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15243299","citation_count":37,"is_preprint":false},{"pmid":"8645250","id":"PMC_8645250","title":"Decreased ET(B) receptor expression in human metastatic melanoma cells.","date":"1996","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8645250","citation_count":36,"is_preprint":false},{"pmid":"17046837","id":"PMC_17046837","title":"Expression and immunolocalization of endothelin peptides and its receptors, ETA and ETB, in the carotid body exposed to chronic intermittent hypoxia.","date":"2006","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/17046837","citation_count":36,"is_preprint":false},{"pmid":"28236341","id":"PMC_28236341","title":"EDNRB mutations cause Waardenburg syndrome type II in the heterozygous state.","date":"2017","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/28236341","citation_count":35,"is_preprint":false},{"pmid":"12799311","id":"PMC_12799311","title":"ETA and ETB receptor function in pancreatitis-associated microcirculatory failure, inflammation, and parenchymal injury.","date":"2003","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12799311","citation_count":35,"is_preprint":false},{"pmid":"18524860","id":"PMC_18524860","title":"ADP-ribosyl cyclase and ryanodine receptors mediate endothelin ETA and ETB receptor-induced renal vasoconstriction in vivo.","date":"2008","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18524860","citation_count":35,"is_preprint":false},{"pmid":"21264540","id":"PMC_21264540","title":"Quantitative analysis of promoter methylation of the EDNRB gene in gastric cancer.","date":"2011","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21264540","citation_count":34,"is_preprint":false},{"pmid":"28779103","id":"PMC_28779103","title":"Epilation induces hair and skin pigmentation through an EDN3/EDNRB-dependent regenerative response of melanocyte stem cells.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28779103","citation_count":33,"is_preprint":false},{"pmid":"12473537","id":"PMC_12473537","title":"ACE inhibition increases expression of the ETB receptor in kidneys of mice with unilateral obstruction.","date":"2003","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12473537","citation_count":33,"is_preprint":false},{"pmid":"18758497","id":"PMC_18758497","title":"Polymorphisms of EDNRB, ATG, and ACE genes in salt-sensitive hypertension.","date":"2008","source":"Canadian journal of physiology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18758497","citation_count":33,"is_preprint":false},{"pmid":"11891690","id":"PMC_11891690","title":"ABCD syndrome is caused by a homozygous mutation in the EDNRB gene.","date":"2002","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11891690","citation_count":32,"is_preprint":false},{"pmid":"8129032","id":"PMC_8129032","title":"Divergent expression of EtA and EtB receptors in response to cyclosporine in mesangial cells.","date":"1994","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/8129032","citation_count":31,"is_preprint":false},{"pmid":"19390510","id":"PMC_19390510","title":"D3 dopamine receptor regulation of ETB receptors in renal proximal tubule cells from WKY and SHRs.","date":"2009","source":"American journal of hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/19390510","citation_count":30,"is_preprint":false},{"pmid":"33919338","id":"PMC_33919338","title":"Endothelin ETB Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33919338","citation_count":29,"is_preprint":false},{"pmid":"28063956","id":"PMC_28063956","title":"Differentiation of Mouse Enteric Nervous System Progenitor Cells Is Controlled by Endothelin 3 and Requires Regulation of Ednrb by SOX10 and ZEB2.","date":"2017","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/28063956","citation_count":29,"is_preprint":false},{"pmid":"31313802","id":"PMC_31313802","title":"A gene regulatory network explains RET-EDNRB epistasis in Hirschsprung disease.","date":"2019","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31313802","citation_count":28,"is_preprint":false},{"pmid":"35110536","id":"PMC_35110536","title":"BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35110536","citation_count":28,"is_preprint":false},{"pmid":"28512356","id":"PMC_28512356","title":"Adamdec1, Ednrb and Ptgs1/Cox1, inflammation genes upregulated in the intestinal mucosa of obese rats, are downregulated by three probiotic strains.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28512356","citation_count":28,"is_preprint":false},{"pmid":"12611392","id":"PMC_12611392","title":"Unique endothelin receptor binding in kidneys of ETB receptor deficient rats.","date":"2003","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12611392","citation_count":28,"is_preprint":false},{"pmid":"15838363","id":"PMC_15838363","title":"ETA receptor blockade attenuates hypertension and decreases reactive oxygen species in ETB receptor-deficient rats.","date":"2004","source":"Journal of cardiovascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15838363","citation_count":28,"is_preprint":false},{"pmid":"31606133","id":"PMC_31606133","title":"Endothelin-1 increases expression and activity of arginase 2 via ETB receptors and is co-expressed with arginase 2 in human atherosclerotic plaques.","date":"2019","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/31606133","citation_count":28,"is_preprint":false},{"pmid":"7921617","id":"PMC_7921617","title":"Effects of selective ETB-receptor stimulation on arterial, venous and capillary functions in cat skeletal muscle.","date":"1994","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/7921617","citation_count":28,"is_preprint":false},{"pmid":"22480514","id":"PMC_22480514","title":"Comparison of human ETA and ETB receptor signalling via G-protein and β-arrestin pathways.","date":"2012","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22480514","citation_count":27,"is_preprint":false},{"pmid":"8587403","id":"PMC_8587403","title":"Identification and function of putative ETB receptor subtypes in the dog kidney.","date":"1995","source":"Journal of cardiovascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/8587403","citation_count":26,"is_preprint":false},{"pmid":"28924375","id":"PMC_28924375","title":"LncRNA AFAP1-AS Functions as a Competing Endogenous RNA to Regulate RAP1B Expression by sponging miR-181a in the HSCR.","date":"2017","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28924375","citation_count":25,"is_preprint":false},{"pmid":"15359489","id":"PMC_15359489","title":"Role of endothelin ETB receptor in the pathogenesis of monocrotaline-induced pulmonary hypertension in rats.","date":"2004","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15359489","citation_count":25,"is_preprint":false},{"pmid":"18564167","id":"PMC_18564167","title":"Identification of aberrant promoter methylation of EDNRB gene in esophageal squamous cell carcinoma.","date":"2008","source":"Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus","url":"https://pubmed.ncbi.nlm.nih.gov/18564167","citation_count":24,"is_preprint":false},{"pmid":"34415188","id":"PMC_34415188","title":"ETB receptor-mediated vasodilation is regulated by estradiol in young women.","date":"2021","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34415188","citation_count":24,"is_preprint":false},{"pmid":"15130886","id":"PMC_15130886","title":"Inotropic effects of ETB receptor stimulation and their modulation by endocardial endothelium, NO, and prostaglandins.","date":"2004","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15130886","citation_count":24,"is_preprint":false},{"pmid":"32394530","id":"PMC_32394530","title":"Role of endothelin receptor type B (EDNRB) in lung adenocarcinoma.","date":"2020","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32394530","citation_count":23,"is_preprint":false},{"pmid":"21858136","id":"PMC_21858136","title":"Expression of PROKR1 and PROKR2 in human enteric neural precursor cells and identification of sequence variants suggest a role in HSCR.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21858136","citation_count":23,"is_preprint":false},{"pmid":"23579558","id":"PMC_23579558","title":"Methylation analysis of EDNRB in human colon tissues of Hirschsprung's disease.","date":"2013","source":"Pediatric surgery international","url":"https://pubmed.ncbi.nlm.nih.gov/23579558","citation_count":23,"is_preprint":false},{"pmid":"32559137","id":"PMC_32559137","title":"Altered endothelial ETB receptor expression in postmenopausal women.","date":"2020","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32559137","citation_count":21,"is_preprint":false},{"pmid":"31351053","id":"PMC_31351053","title":"Endothelins (EDN1, EDN2, EDN3) and their receptors (EDNRA, EDNRB, EDNRB2) in chickens: Functional analysis and tissue distribution.","date":"2019","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31351053","citation_count":21,"is_preprint":false},{"pmid":"17212812","id":"PMC_17212812","title":"Protein kinase C inhibition attenuates vascular ETB receptor upregulation and decreases brain damage after cerebral ischemia in rat.","date":"2007","source":"BMC neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17212812","citation_count":21,"is_preprint":false},{"pmid":"24633486","id":"PMC_24633486","title":"Effect of SNP polymorphisms of EDN1, EDNRA, and EDNRB gene on ischemic stroke.","date":"2014","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/24633486","citation_count":20,"is_preprint":false},{"pmid":"28764936","id":"PMC_28764936","title":"TRPC3- and ETB receptor-mediated PI3K/AKT activation induces vasogenic edema formation following status epilepticus.","date":"2017","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/28764936","citation_count":20,"is_preprint":false},{"pmid":"9380020","id":"PMC_9380020","title":"Identification and characterization of a novel endothelin receptor that binds both ETA- and ETB-selective ligands.","date":"1997","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/9380020","citation_count":20,"is_preprint":false},{"pmid":"18784135","id":"PMC_18784135","title":"Expression and function of ETA and ETB receptors in SSc.","date":"2008","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18784135","citation_count":19,"is_preprint":false},{"pmid":"9371807","id":"PMC_9371807","title":"Molecular characterization of four induced alleles at the Ednrb locus.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9371807","citation_count":19,"is_preprint":false},{"pmid":"29601873","id":"PMC_29601873","title":"Homocysteine up-regulates ETB receptors via suppression of autophagy in vascular smooth muscle cells.","date":"2018","source":"Microvascular research","url":"https://pubmed.ncbi.nlm.nih.gov/29601873","citation_count":19,"is_preprint":false},{"pmid":"18187958","id":"PMC_18187958","title":"Epigenetic and genetic alterations of the EDNRB gene in nasopharyngeal carcinoma.","date":"2008","source":"Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18187958","citation_count":18,"is_preprint":false},{"pmid":"15834508","id":"PMC_15834508","title":"Low RET mutation frequency and polymorphism analysis of the RET and EDNRB genes in patients with Hirschsprung disease in Taiwan.","date":"2005","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15834508","citation_count":18,"is_preprint":false},{"pmid":"24398995","id":"PMC_24398995","title":"Valproic acid substantially downregulated genes folr1, IGF2R, RGS2, COL6A3, EDNRB, KLF6, and pax-3, N-acetylcysteine alleviated most of the induced gene alterations in chicken embryo model.","date":"2013","source":"Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie","url":"https://pubmed.ncbi.nlm.nih.gov/24398995","citation_count":18,"is_preprint":false},{"pmid":"16328051","id":"PMC_16328051","title":"Aberrant promoter methylation of EDNRB in lung cancer in Taiwan.","date":"2006","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/16328051","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52030,"output_tokens":7057,"usd":0.130972,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16218,"output_tokens":4254,"usd":0.09372,"stage2_stop_reason":"end_turn"},"total_usd":0.224692,"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\": 1991,\n      \"finding\": \"Human EDNRB cDNA was cloned and functionally expressed in COS cells, demonstrating that the receptor binds endothelin isopeptides (ET-1 and ET-3) with approximately equal potency and couples to intracellular Ca2+ transients ([Ca2+]i increases), establishing its non-isopeptide-selective pharmacology.\",\n      \"method\": \"cDNA cloning, radioligand binding (125I-ET-1 displacement), Ca2+ imaging in transfected COS cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct reconstitution of receptor function via cDNA transfection with binding and signaling assays; foundational cloning paper\",\n      \"pmids\": [\"1713452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"In vivo pharmacological activation of EDNRB with the selective agonist sarafotoxin S6c produces both a transient vasodepressor (endothelium-dependent vasodilation) and a subsequent sustained pressor response with renal and mesenteric vasoconstriction, demonstrating that EDNRB mediates both vasodilation and vasoconstriction in vivo.\",\n      \"method\": \"In vivo pharmacology in rats using selective ETB agonist sarafotoxin S6c; blood pressure and vascular resistance measurements\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct in vivo pharmacological dissection with selective agonist, replicated across multiple vascular beds\",\n      \"pmids\": [\"1323294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"EDNRB protein localizes to endothelial cells in multiple tissues (kidney, adrenal gland, lung, cerebellum, pituitary gland) as determined by immunohistochemistry using a receptor-specific antiserum that immunoprecipitates only ETB and not ETA; tissue-specific ETB:ETA ratios were quantified (e.g., lung ~70% ETB, testis <2% ETB).\",\n      \"method\": \"Immunohistochemistry, Western blot, and immunoprecipitation with subtype-specific antiserum\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoprecipitation and immunohistochemistry with specific antiserum, single lab\",\n      \"pmids\": [\"8476120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Both ETA and ETB receptors mediate contraction in human vascular smooth muscle cells; EDNRB-specific stimulation with sarafotoxin S6c induces contraction in ETA-blocked vessels, and ETB mRNA was detected by Northern blot in smooth muscle cells, establishing that smooth muscle ETB receptors are functionally contractile.\",\n      \"method\": \"Pharmacological antagonism (FR139317, BQ-123, bosentan), sarafotoxin S6c agonism, ETB receptor downregulation by prolonged sarafotoxin S6c preincubation, Northern blot for ETB mRNA\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal pharmacological methods in human tissue with ETB downregulation controls; replicated across multiple vessel types\",\n      \"pmids\": [\"8124808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Both ETA and ETB receptors couple to the MAPK cascade (activation of p42 MAPK and MAPKK) and stimulate cell proliferation ([3H]thymidine uptake), as demonstrated in CHO cells transfected with either human ETA or ETB cDNA; ET isopeptide potency differences reflect receptor binding affinities.\",\n      \"method\": \"cDNA transfection of CHO cells, MAPK activity assays, [3H]thymidine incorporation\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct reconstitution in transfected cells with multiple signaling readouts; clean receptor-specific comparison\",\n      \"pmids\": [\"7943276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"ETB receptor activation (by ET-1 in OKPETB6 cells overexpressing EDNRB) stimulates NHE3 (Na+/H+ exchanger isoform 3) activity via tyrosine kinase pathways; ET-1 induces tyrosine phosphorylation of paxillin (68 kDa) and p125FAK via ETB, and this focal adhesion kinase pathway is not required for antiporter activation, whereas a membrane-associated 210 kDa phosphoprotein may mediate 50% of the NHE3 activation.\",\n      \"method\": \"Na+/H+ antiporter activity assays, immunoprecipitation, tyrosine phosphorylation assays, cytochalasin D disruption of focal adhesions in OKP cells overexpressing ETB\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (antiporter activity, immunoprecipitation, pharmacological dissection) in a well-defined cell system\",\n      \"pmids\": [\"8843705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"EDNRB activation by ET-1 induces NHE3 phosphorylation on multiple threonine and serine residues in OKP cells expressing ETB receptors (but not ETA receptors); phosphorylation is maximal at 15–30 min with 1 nM ET-1 and correlates temporally and in concentration dependence with NHE3 activation, suggesting phosphorylation mediates ETB-stimulated NHE3 activity.\",\n      \"method\": \"Na+/H+ antiporter activity assays, immunoprecipitation, SDS-PAGE mobility shift, alkaline phosphatase treatment, phosphoamino acid analysis in OKP cells with ETB or ETA receptors\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in receptor-transfected cells with biochemical validation of phosphorylation; multiple orthogonal methods\",\n      \"pmids\": [\"10199826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Genetic and pharmacological disruption of EDNRB in mice elevates arterial blood pressure by ~20 mmHg; this depressor effect of endogenous ET acting through ETB is mediated in part by tonic prostaglandin production (attenuated by indomethacin but not by L-NMMA), not through respiratory control or ET clearance.\",\n      \"method\": \"ETB knockout/hypomorphic mouse model (ETB-/s vs ETB+/s), selective ETB antagonist BQ-788, selective ETA antagonist BQ-123, indomethacin and L-NMMA pharmacology, blood pressure telemetry\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function combined with pharmacological dissection of signaling mediators; multiple mechanistic controls\",\n      \"pmids\": [\"10198387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The EDNRB gene 5' CpG island undergoes tissue-specific methylation that silences transcription; low methylation in a small region within the 5' region correlates with expression of the 5'-most transcript, and treatment with 5-aza-2'-deoxycytidine reactivates all four EDNRB transcripts, establishing promoter methylation as a regulatory mechanism.\",\n      \"method\": \"Bisulfite sequencing of 11 individual CpG sites, methylation-sensitive restriction fingerprinting, 5-aza-2'-deoxycytidine demethylation, RT-PCR for transcript expression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct bisulfite sequencing plus pharmacological demethylation with transcript rescue; multiple orthogonal methods\",\n      \"pmids\": [\"11309363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EDNRB activation specifically enhances RET signaling-induced proliferation of uncommitted ENS progenitors; EDNRB and RET signaling have opposing (antagonistic) roles in ENS progenitor migration; protein kinase A (PKA) is a key molecular integrator of EDNRB and RET pathway crosstalk during enteric nervous system development.\",\n      \"method\": \"Primary ENS progenitor culture assays with selective receptor agonists/antagonists, PKA inhibitor/activator pharmacology, proliferation and migration assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct cellular assays with pharmacological dissection of both pathways and PKA mechanism; multiple readouts\",\n      \"pmids\": [\"14659090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Genetic titration of Ednrb in Ret kinase-null heterozygous mice demonstrates tissue-specific epistasis: EDNRB-RET interaction is restricted to the enteric nervous system and does not affect renal, melanocyte, or retinal choroid development; the degree of Ednrb dosage determines both penetrance and sex bias of aganglionosis.\",\n      \"method\": \"Two-locus noncomplementation assay in mice, allelic series at Ednrb in Ret+/- background, phenotypic analysis of enteric, renal, and coat color phenotypes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in multiple allelic combinations in mice with tissue-specific phenotypic readouts\",\n      \"pmids\": [\"12574515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Renal medullary EDNRB stimulation (by sarafotoxin S6c infusion) induces diuresis and natriuresis through a NOS1 → cGMP → PKG signaling cascade; S6c-induced increases in urine flow, sodium excretion, and medullary cGMP were absent in ETB receptor-deficient rats and were abolished by selective NOS1 inhibitor or PKG inhibitor.\",\n      \"method\": \"In vivo renal medullary infusion in anesthetized rats, ETB-deficient rat model, selective NOS1 inhibitor (N(G)-propyl-L-arginine), PKG inhibitor, cGMP measurement, urine flow and sodium excretion\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function combined with selective pharmacological pathway inhibition; multiple mechanistic steps confirmed\",\n      \"pmids\": [\"18305094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ET-1 impairs alveolar fluid reabsorption via endothelial EDNRB: ETB (not ETA) blockade prevents ET-1-induced decrease in alveolar fluid reabsorption; ET-1 acts on endothelial EDNRB to produce NO (cGMP-independent mechanism) that in turn decreases Na,K-ATPase activity and plasma membrane abundance in alveolar epithelial cells; transgenic rats deficient in pulmonary vascular ETB receptors are protected.\",\n      \"method\": \"Isolated perfused rat lung, ETB-deficient transgenic rats, endothelial-epithelial cell co-culture, ETB/ETA antagonist pharmacology, Na,K-ATPase activity assay, NO synthase inhibitor L-NAME\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function plus pharmacological dissection plus mechanistic cell biology across multiple experimental systems\",\n      \"pmids\": [\"18948426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Endothelial cell-specific EDNRB is the primary site responsible for clearance of circulating ET-1; endothelial-specific ETB knockout mice show impaired 125I-ET-1 clearance and elevated plasma ET-1, while ETB binding is selectively decreased in EC-rich tissues (lung, liver, kidney).\",\n      \"method\": \"Endothelial cell-specific Cre-lox ETB knockout mice, 125I-ET-1 clearance assay, autoradiography, immunocytochemistry, RT-PCR, selective ETB antagonist A192621\",\n      \"journal\": \"Canadian journal of physiology and pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic knockout with direct clearance assay and pharmacological confirmation\",\n      \"pmids\": [\"20628430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"After status epilepticus, EDNRB activation drives vasogenic edema by stimulating endothelial eNOS, increasing MMP-9 activity, and degrading the tight junction protein ZO-1 in endothelial cells; ETB antagonist BQ788 attenuates SE-induced vasogenic edema by blocking eNOS-MMP-9-ZO-1 degradation.\",\n      \"method\": \"In vivo rat SE model, ETB antagonist BQ788, immunohistochemistry/immunofluorescence for tight junction proteins, MMP-9 activity assay, eNOS activation assay\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological loss-of-function with defined molecular pathway; single lab\",\n      \"pmids\": [\"26232046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of human EDNRB in ligand-free and ET-1-bound forms reveals that transmembrane helices 1, 2, 6, and 7 move to envelop the entire ET-1 peptide in a virtually irreversible manner; agonist-induced conformational changes propagate to the cytoplasmic G-protein coupling interface and induce flexibility in TM6; mutation analysis defines the mechanism for ET-1 versus ET-3 isopeptide selectivity.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, functional Ca2+ assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with mutagenesis validation; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"27595334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EDNRB signaling in melanocyte stem cells promotes their proliferation and differentiation to regenerate hair and epidermal melanocytes; this effect requires active Wnt signaling initiated by Wnt ligand secretion from the hair follicle epithelial niche, and Wnt-dependent EDNRB signaling can rescue defects caused by Mc1R loss.\",\n      \"method\": \"Genetic loss-of-function (EdnrB knockout in melanocyte stem cells), Wnt signaling inhibition/activation, in vivo melanocyte regeneration assays, Mc1R mutant rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic knockout with pathway epistasis (Wnt requirement) and functional rescue\",\n      \"pmids\": [\"27134165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Epilation induces endogenous EDN3 upregulation in the dermal papilla, secondary hair germ cells, and epidermis; genetic and pharmacological disruption of EDNRB blocks melanocyte stem cell activation, follicular and epidermal melanocyte regeneration, and skin/hair hyperpigmentation after epilation.\",\n      \"method\": \"In vivo mouse epilation model, EDNRB genetic disruption (conditional knockout), pharmacological EDNRB blockade, immunofluorescence for melanocyte markers\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function plus pharmacological confirmation with defined upstream ligand (EDN3) and functional readouts\",\n      \"pmids\": [\"28779103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EDNRB heterozygous missense mutations cause Waardenburg syndrome type II (pigmentation/hearing loss without Hirschsprung disease) with dominant incomplete penetrance; cellular studies showed that each of six identified mutations impairs subcellular localization of EDNRB or induces defective downstream signaling.\",\n      \"method\": \"Exome sequencing, family segregation analysis, cellular localization studies (immunofluorescence), downstream signaling assays in transfected cells\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cellular studies of subcellular localization and signaling for each mutation; single lab\",\n      \"pmids\": [\"28236341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EDN3-mediated EDNRB signaling prevents premature neuronal differentiation of enteric nervous system progenitor cells; this requires two copies of Zeb2 (ZEB2). SOX10 and ZEB2 directly activate the EDNRB promoter (confirmed by chromatin immunoprecipitation and transactivation assays), and overexpression of EDNRB in Zeb2-heterozygous EPCs restores EDN3-mediated inhibition of differentiation.\",\n      \"method\": \"Enteric progenitor cell cultures, Zeb2 and Edn3 mutant mouse crosses, chromatin immunoprecipitation, transactivation assays, retroviral EDNRB rescue, immunocytochemistry\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP + transactivation assays + genetic rescue across multiple experimental systems; multiple orthogonal methods\",\n      \"pmids\": [\"28063956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structures of human EDNRB bound to ET-3 and the partial agonist IRL1620 reveal that disruption of water-mediated interactions between W6.48 and D2.50 is critical for full receptor activation; IRL1620 partially preserves these hydrogen-bonding interactions, explaining its partial agonism confirmed by functional analysis.\",\n      \"method\": \"X-ray crystallography of ETB-ET3 and ETB-IRL1620 complexes, site-directed mutagenesis, functional Ca2+ signaling assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with mutagenesis and functional validation; mechanistic explanation of partial agonism\",\n      \"pmids\": [\"30413709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EDNRB transcription in the enteric nervous system is directly regulated by transcription factors GATA2, SOX10, and NKX2.5; RET and EDNRB share GATA2 and SOX10 as regulators, and these TFs are in turn controlled by EDNRB and RET in a dose-dependent feedback manner, explaining RET-EDNRB epistasis in Hirschsprung disease.\",\n      \"method\": \"Human and mouse cellular models, ChIP assays, reporter gene assays, animal models of EDNRB and RET expression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus reporter assays plus genetic animal models; multiple orthogonal methods across human and mouse systems\",\n      \"pmids\": [\"31313802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"D3 dopamine receptors physically interact with EDNRB (co-immunoprecipitation) in renal proximal tubule cells; D3 receptor activation increases ETB receptor expression (calcium-dependent, blocked by nicardipine) in WKY rats and augments ETB-mediated inhibition of Na+/K+-ATPase activity; this D3-ETB interaction is impaired in spontaneously hypertensive rats.\",\n      \"method\": \"Co-immunoprecipitation, immunoblotting, RT-PCR, Na+/K+-ATPase activity assay, selective agonist/antagonist pharmacology\",\n      \"journal\": \"American journal of hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-immunoprecipitation plus functional assays; single lab, two orthogonal methods\",\n      \"pmids\": [\"19390510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ETB receptor activation mediates apoptosis of retinal ganglion cells (RGC-5 cells) via cytochrome c release from mitochondria and JNK phosphorylation; ET-1-induced apoptosis was markedly attenuated in ETB receptor-deficient rats and by ETB antagonist BQ788 in cultured cells.\",\n      \"method\": \"Flow cytometry, cytochrome c release assay, JNK phosphorylation assay, ETB-deficient rat model, BQ788 pharmacology\",\n      \"journal\": \"Canadian journal of physiology and pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function (ETB-deficient rats) plus pharmacological blockade plus mechanistic pathway assays; single lab\",\n      \"pmids\": [\"18516102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"A critical proline residue in the fifth transmembrane domain of EDNRB is required for function in vivo (Ednrb27Pub allele); loss of authentic Ednrb mRNA (Ednrb3Chlo allele, gross genomic deletion) or reduced mRNA level (Ednrb17FrS) causes juvenile lethality and pigmentation defects, demonstrating that EDNRB expression level is dosage-sensitive for melanocyte development.\",\n      \"method\": \"Molecular characterization of four ENU/radiation-induced mouse Ednrb alleles by sequencing, mRNA analysis (Northern blot/RT-PCR), and phenotypic analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent alleles with molecular characterization and in vivo phenotypic validation; establishes structure-function at specific domain\",\n      \"pmids\": [\"9371807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-124-3p directly targets EDNRB (confirmed by dual-luciferase reporter assay); miR-124-3p suppresses EDNRB expression and thereby inhibits bladder cancer cell proliferation and induces apoptosis; EDNRB siRNA phenocopies miR-124-3p mimic effects.\",\n      \"method\": \"Dual-luciferase reporter assay, qRT-PCR, Western blot, siRNA knockdown, cell proliferation (MTS/colony assay), flow cytometry apoptosis assay, nude mouse tumorigenicity assay\",\n      \"journal\": \"Archives of medical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter plus knockdown rescue with functional readouts; single lab\",\n      \"pmids\": [\"31572460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Homocysteine upregulates EDNRB in vascular smooth muscle cells by inhibiting autophagy via the AMPK/mTOR signaling pathway; AMPK activator (AICAR) or mTOR inhibitor (rapamycin) reverses Hcy-induced ETB receptor upregulation and contractile responses, while mTOR activator (MHY1485) restores the effect.\",\n      \"method\": \"Rat superior mesenteric artery myograph, Western blot, immunofluorescence for LC3B (autophagy marker), AICAR/rapamycin/MHY1485 pharmacology\",\n      \"journal\": \"Microvascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional vascular assay plus molecular pathway analysis with pharmacological pathway rescue; single lab\",\n      \"pmids\": [\"29601873\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EDNRB is a class A GPCR that, upon binding endothelins (ET-1, ET-2, ET-3 with equal potency), undergoes a ligand-induced conformational change in which TM helices 1, 2, 6, and 7 envelop the peptide—disrupting a W6.48–D2.50 water-mediated interaction to enable full G-protein coupling—and signals through Ca2+ mobilization, MAPK activation, tyrosine kinase pathways (including FAK/paxillin), PKA, and NOS1/cGMP/PKG; endothelial EDNRB is the primary site for ET-1 clearance from the circulation and mediates vasodilation (via NO/prostaglandins), while smooth muscle EDNRB mediates vasoconstriction; in the kidney it promotes natriuresis via NOS1-cGMP-PKG; in ENS and melanocyte development, EDNRB cooperates with RET (integrated through a shared GATA2/SOX10 gene regulatory network) and with Wnt signaling to control neural crest progenitor proliferation, migration, and differentiation timing, with EDNRB expression itself directly transcriptionally regulated by SOX10, ZEB2, GATA2, and NKX2.5; loss-of-function mutations cause Hirschsprung disease and Waardenburg syndrome through failure of enteric neuron and melanocyte colonization, while promoter CpG hypermethylation silences EDNRB in multiple cancers.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EDNRB is a class A G-protein-coupled receptor that binds the endothelin isopeptides ET-1 and ET-3 with approximately equal potency and couples to intracellular Ca2+ mobilization, defining its non-isopeptide-selective pharmacology [#0]. Crystal structures of ligand-free and ET-1-, ET-3-, and partial-agonist-bound receptor show that transmembrane helices 1, 2, 6, and 7 close around the peptide in an essentially irreversible manner, and that disruption of a water-mediated W6.48\\u2013D2.50 interaction propagates conformational change to the cytoplasmic G-protein interface to drive full activation [#15, #20]. Downstream of receptor engagement, EDNRB activates the MAPK cascade and proliferation [#4], tyrosine-kinase pathways including FAK and paxillin that regulate the Na+/H+ exchanger NHE3 [#5, #6], and NOS/cGMP/PKG signaling [#11]. The receptor exerts opposing vascular actions in vivo, mediating both endothelium-dependent vasodilation and sustained vasoconstriction [#1, #3]. Endothelial EDNRB is the primary clearance site for circulating ET-1 [#13] and drives prostaglandin- and NO-dependent depressor tone, vasogenic edema through eNOS\\u2013MMP-9\\u2013ZO-1 degradation, and modulation of alveolar fluid reabsorption [#7, #12, #14], while renal medullary EDNRB promotes diuresis and natriuresis via a NOS1\\u2192cGMP\\u2192PKG cascade [#11]. In neural crest development EDNRB controls enteric progenitor proliferation, migration, and differentiation timing, integrating with RET signaling through PKA and a shared GATA2/SOX10 transcriptional network, with its own expression directly activated by SOX10, ZEB2, GATA2, and NKX2.5 [#9, #19, #21], and it cooperates with Wnt signaling to drive melanocyte stem cell activation and regeneration [#16, #17]. Loss-of-function and dosage-sensitive mutations of EDNRB cause Hirschsprung disease and Waardenburg syndrome type II through failed enteric neuron and melanocyte colonization [#18, #24], and promoter CpG-island hypermethylation silences EDNRB transcription [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established that EDNRB is a functional endothelin receptor with non-selective isopeptide pharmacology, distinguishing it from the ETA subtype and defining its core signaling output.\",\n      \"evidence\": \"cDNA cloning and expression in COS cells with radioligand binding and Ca2+ imaging\",\n      \"pmids\": [\"1713452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of ligand binding\", \"G-protein coupling specificity not defined\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Showed that a single EDNRB-selective agonist produces both vasodilation and vasoconstriction in vivo, revealing dual and opposing vascular roles for one receptor.\",\n      \"evidence\": \"In vivo rat pharmacology with selective ETB agonist sarafotoxin S6c and hemodynamic measurements\",\n      \"pmids\": [\"1323294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell types responsible for each response not distinguished\", \"Downstream signaling mediators undefined\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Localized EDNRB protein predominantly to endothelial cells across tissues and quantified tissue-specific ETB:ETA ratios, framing where the receptor acts.\",\n      \"evidence\": \"Immunohistochemistry, Western blot, and immunoprecipitation with subtype-specific antiserum\",\n      \"pmids\": [\"8476120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab antiserum-based localization\", \"Non-endothelial expression sites not fully mapped\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Defined intracellular signaling outputs by showing EDNRB couples to the MAPK cascade and drives proliferation, and that smooth muscle ETB receptors are functionally contractile.\",\n      \"evidence\": \"CHO cDNA transfection with MAPK and thymidine incorporation assays; human vessel pharmacology with ETB downregulation controls and Northern blot\",\n      \"pmids\": [\"7943276\", \"8124808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between MAPK activation and physiological contraction not established\", \"G-protein identity not defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Connected EDNRB to renal ion transport by showing ETB-specific activation stimulates NHE3 via tyrosine-kinase pathways including FAK/paxillin and direct NHE3 phosphorylation.\",\n      \"evidence\": \"Na+/H+ antiporter activity, immunoprecipitation, phosphorylation and mobility-shift analyses in OKP cells expressing ETB vs ETA\",\n      \"pmids\": [\"8843705\", \"10199826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the 210 kDa phosphoprotein mediator unknown\", \"Kinase acting directly on NHE3 not identified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated in vivo that endogenous ETB tone lowers blood pressure largely through prostaglandin production, dissecting the depressor mechanism.\",\n      \"evidence\": \"ETB hypomorphic mice with selective antagonists, indomethacin and L-NMMA, and blood pressure telemetry\",\n      \"pmids\": [\"10198387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular source of prostaglandins not pinpointed\", \"Relationship to ET clearance not resolved here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed how EDNRB integrates with RET during enteric nervous system development, identifying PKA as the crosstalk node and demonstrating tissue-restricted genetic epistasis.\",\n      \"evidence\": \"Primary ENS progenitor assays with PKA pharmacology; two-locus noncomplementation and allelic-series genetics in Ret-null mice\",\n      \"pmids\": [\"14659090\", \"12574515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of opposing migration vs proliferation effects unresolved\", \"Direct PKA substrates not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined organ-specific EDNRB signaling cascades: NOS1-cGMP-PKG-driven natriuresis in renal medulla, NO-dependent suppression of alveolar Na,K-ATPase, and a mitochondrial apoptotic pathway in retinal cells.\",\n      \"evidence\": \"In vivo renal infusion and lung perfusion in ETB-deficient rats with NOS/PKG inhibitors; flow cytometry and cytochrome c/JNK assays in RGC-5 cells\",\n      \"pmids\": [\"18305094\", \"18948426\", \"18516102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apoptosis pathway shown in a single lab\", \"Cell-type specificity of NO source in lung not fully resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established endothelial EDNRB as the principal clearance receptor for circulating ET-1 using cell-type-specific genetics.\",\n      \"evidence\": \"Endothelial-specific Cre-lox ETB knockout mice with 125I-ET-1 clearance, autoradiography, and selective antagonist\",\n      \"pmids\": [\"20628430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular fate of internalized ET-1 not traced\", \"Contribution to circulating ET-1 setpoint in disease undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural mechanism of activation, showing TM1/2/6/7 envelopment of endothelin and propagation of conformational change to the G-protein interface.\",\n      \"evidence\": \"X-ray crystallography of ligand-free and ET-1-bound EDNRB with mutagenesis and Ca2+ assays\",\n      \"pmids\": [\"27595334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No active-state complex with bound G protein\", \"Dynamics of irreversible binding not captured\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed EDNRB drives melanocyte stem cell proliferation and regeneration in a Wnt-dependent manner, placing it within a niche signaling network.\",\n      \"evidence\": \"Melanocyte-stem-cell-specific EdnrB knockout, Wnt modulation, and Mc1R mutant rescue in vivo\",\n      \"pmids\": [\"27134165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular point of Wnt-EDNRB convergence not defined\", \"Downstream effectors in stem cells unidentified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected EDNRB to disease and transcriptional control: WS2-causing mutations impair localization/signaling, EDN3-EDNRB prevents premature ENS differentiation, and SOX10/ZEB2 directly activate the EDNRB promoter.\",\n      \"evidence\": \"Exome sequencing and cellular assays of WS2 mutations; epilation-induced EDN3 in vivo; ChIP, transactivation, and retroviral rescue in enteric progenitors\",\n      \"pmids\": [\"28236341\", \"28779103\", \"28063956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"WS2 functional studies from a single lab\", \"How differentiation timing is mechanistically held in check unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped the transcriptional regulatory logic explaining RET-EDNRB epistasis, showing GATA2, SOX10, and NKX2.5 directly drive EDNRB in a dose-dependent feedback network shared with RET.\",\n      \"evidence\": \"ChIP and reporter assays in human and mouse cellular models with animal expression analyses\",\n      \"pmids\": [\"31313802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative dynamics of the feedback loop undefined\", \"Tissue specificity of NKX2.5 input not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EDNRB's full active-state signaling complexes (G protein, arrestin) are organized, and how cell-type-specific transcriptional and post-transcriptional control (methylation, miRNA, autophagy) is integrated to set receptor abundance in disease, remains incompletely defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No active-state G-protein-bound structure in the corpus\", \"Integration of methylation, miR-124-3p, and AMPK/mTOR control into a single regulatory model not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 15]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 16, 19]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [1, 3, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EDN1\", \"EDN3\", \"RET\", \"DRD3\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}