Affinage

EDNRB

Endothelin receptor type B · UniProt P24530

Length
442 aa
Mass
49.6 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EDNRB is a class A G-protein-coupled receptor for endothelin peptides that mediates vasodilation, vasoconstriction, natriuresis, and diuresis depending on tissue context, and is essential for neural crest-derived melanocyte and enteric neuron development. Crystal structures show that agonist binding causes transmembrane helices 1, 2, 6, and 7 to envelop the endothelin peptide, disrupting a W6.48–D2.50 water-mediated hydrogen-bonding network to propagate conformational changes to the G-protein interface; Asp147 in TM2 is required for phospholipase C activation but not ligand binding (PMID:27595334, PMID:30413709, PMID:7698331). Activated EDNRB signals through Ca²⁺ and tyrosine kinase pathways to phosphorylate NHE3 and stimulates a NO→cGMP→PKG cascade that drives renal sodium and water excretion and endothelium-dependent vasodilation, undergoes rapid agonist-induced phosphorylation producing desensitization kinetically distinct from ETA, and genetically interacts with RET during enteric nervous system colonization under the transcriptional control of SOX10, ZEB2, GATA2, and NKX2.5—with loss-of-function mutations causing Hirschsprung disease and pigmentation defects (PMID:18305094, PMID:9341224, PMID:12355085, PMID:28063956). EDNRB promoter CpG hypermethylation silences expression in multiple cancers, reversible by demethylating agents (PMID:11309363).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1992 High

    Establishing that EDNRB is a dual-function vascular receptor: selective ETB agonists demonstrated that a single receptor subtype mediates both transient endothelium-dependent vasodilation and sustained vasoconstriction, and that the vasodilatory arm operates through an NO→cGMP pathway.

    Evidence In vivo selective agonist (sarafotoxin S6c) pharmacology in rats; glomerular cGMP assays with NOS/guanylate cyclase inhibitors

    PMID:1323294 PMID:1336308

    Open questions at the time
    • Downstream signaling intermediates between EDNRB and NOS activation were not identified
    • Cell-type-specific contributions (endothelial vs. smooth muscle) not genetically separated
  2. 1995 High

    Defining the tissue distribution and signal-transduction requirements of EDNRB: immunohistochemistry localized the receptor predominantly to vascular endothelium across organs, mutagenesis of Asp147 in TM2 separated ligand binding from PLC coupling, and human studies confirmed ETB-mediated vasoconstriction in resistance and capacitance vessels.

    Evidence Subtype-specific antiserum immunohistochemistry; site-directed mutagenesis of human ETB in COS cells with IP accumulation and radioligand binding; intra-arterial selective agonist infusion in human subjects

    PMID:7634449 PMID:7698331 PMID:8476120

    Open questions at the time
    • Structural basis for why Asp147 couples to G-protein signaling was unknown
    • Endothelial versus smooth muscle ETB contributions not genetically dissected in vivo
  3. 1996 High

    Identifying the downstream effector pathways by which EDNRB regulates epithelial Na⁺/H⁺ exchange: EDNRB-specific activation of NHE3 proceeds through parallel Ca²⁺-dependent and tyrosine kinase (p210/paxillin/p125FAK) pathways, revealing a bifurcating intracellular signaling architecture.

    Evidence Pharmacological inhibitors and immunoprecipitation in OKP cells stably expressing ETB

    PMID:8843705

    Open questions at the time
    • Identity of the p210 tyrosine kinase was unknown
    • Whether these pathways operate in native renal tubule cells was not shown
  4. 1997 High

    Demonstrating that EDNRB undergoes rapid agonist-induced phosphorylation causing fast desensitization distinct from ETA, and that a TM5 proline is critical for receptor function in neural crest development.

    Evidence Phosphorylation/IP accumulation/internalization assays in HEK cells; molecular characterization of radiation/chemical mutagenesis alleles in mice with white coat/megacolon phenotype

    PMID:9341224 PMID:9371807

    Open questions at the time
    • Kinases responsible for EDNRB phosphorylation were not identified
    • Whether the TM5 proline mutation affects folding versus signaling was unresolved
  5. 1999 High

    Establishing EDNRB as a tonic vasodepressor: gene-targeted ETB-knockout mice showed ~20 mmHg elevated blood pressure, with the depressor effect partly mediated by prostacyclin rather than NO, and EDNRB-specific NHE3 phosphorylation was mapped to multiple Thr/Ser residues.

    Evidence ETB gene-targeted mice with selective pharmacological dissection; immunoprecipitation and alkaline phosphatase in OKP-ETB cells

    PMID:10198387 PMID:10199826

    Open questions at the time
    • Specific NHE3 phosphorylation sites were not individually mutated
    • Relative contribution of renal versus vascular EDNRB to blood pressure was unresolved
  6. 2000 High

    Delineating the renal tubular mechanism: EDNRB on thick ascending limb cells decreases NaCl reabsorption through Ca²⁺-dependent NOS activation, and big-ET-1-induced natriuresis/diuresis is abolished by selective ETB blockade or NOS inhibition.

    Evidence Isolated tubule perfusion with BQ-788/L-NAME; in vivo ETB antagonist and NOS inhibitor infusion in anesthetized rats

    PMID:10720587 PMID:10919853

    Open questions at the time
    • NOS isoform responsible in the thick ascending limb was not specified
    • Whether EDNRB acts on apical or basolateral membrane was not determined
  7. 2001 Medium

    Revealing epigenetic silencing of EDNRB: promoter CpG island methylation was shown to repress all four EDNRB transcripts, with demethylation restoring expression, and EDNRB-dependent prostacyclin generation was found to inhibit platelet aggregation.

    Evidence Bisulfite sequencing and 5-aza-dC treatment in normal and tumor cells; ex vivo platelet aggregation with selective ETB agonist/antagonist and COX inhibitors

    PMID:11181435 PMID:11309363

    Open questions at the time
    • Cancer types and in vivo consequences of EDNRB methylation were not broadly surveyed
    • Whether COX-2-dependent prostacyclin is the sole antiplatelet mediator was not settled
  8. 2002 High

    Establishing genetic epistasis between EDNRB and RET in Hirschsprung disease: intercross of Ret-null and Ednrb-hypomorphic mice produced non-complementation of aganglionosis, placing both genes in a shared pathway for enteric nervous system colonization.

    Evidence Genome-wide association in Mennonite trios; mouse Ret/Ednrb intercross epistasis analysis

    PMID:12355085

    Open questions at the time
    • Molecular mechanism of RET–EDNRB pathway convergence was unknown
    • Whether the epistasis is cell-autonomous in neural crest cells was not shown
  9. 2006 High

    Revealing that EDNRB and Sox10 genetically interact to promote neural crest cell survival: double-mutant mice showed enhanced aganglionosis and increased apoptosis in vagal neural crest cells, linking EDNRB signaling to anti-apoptotic function during gut colonization.

    Evidence Sox10/Ednrb double-mutant mouse phenotypic analysis with apoptosis quantification

    PMID:16650841

    Open questions at the time
    • Anti-apoptotic effectors downstream of EDNRB in neural crest cells were not identified
    • Whether the apoptosis phenotype is cell-autonomous was not definitively resolved
  10. 2008 High

    Refining the renal signaling cascade and identifying a pulmonary paracrine function: medullary EDNRB signals through NOS1→cGMP→PKG to drive natriuresis/diuresis, while pulmonary endothelial EDNRB impairs alveolar fluid clearance via NO-dependent (cGMP-independent) downregulation of epithelial Na,K-ATPase.

    Evidence In vivo renal infusion in ETB-deficient rats with NOS1/PKG inhibitors; isolated perfused lung from ETB-deficient rats with co-culture and Na,K-ATPase assays

    PMID:18305094 PMID:18948426

    Open questions at the time
    • The cGMP-independent NO effector in alveolar epithelium was not identified
    • How NOS1 versus eNOS are differentially engaged across tissues was not addressed
  11. 2016 High

    Solving the structural basis of endothelin recognition: the crystal structure of EDNRB in apo and ET-1-bound forms showed that TM1/2/6/7 move to envelop the entire peptide, creating near-irreversible binding, and revealed flexibility in TM6 linked to G-protein coupling.

    Evidence X-ray crystallography with mutation analysis (Nature)

    PMID:27595334

    Open questions at the time
    • Active-state structure with a G-protein or arrestin was not obtained
    • Structural basis for isopeptide selectivity at the single-residue level was incompletely resolved
  12. 2017 High

    Elucidating antagonist mechanisms and transcriptional control of EDNRB: crystal structures showed bosentan blocks TM6 inward movement while Na⁺ acts as a weak negative allosteric modulator; SOX10 and ZEB2 were shown to directly activate the EDNRB promoter, with EDNRB functioning downstream of ZEB2 to inhibit premature neuronal differentiation of enteric progenitors.

    Evidence X-ray crystallography of bosentan- and K-8794-bound EDNRB; ChIP, transactivation, and retroviral EDNRB rescue in Zeb2-heterozygous enteric progenitor cultures

    PMID:28063956 PMID:28805809

    Open questions at the time
    • Whether Na⁺ allosteric modulation is physiologically relevant was not established
    • Full enhancer/promoter architecture governing tissue-specific EDNRB expression was not mapped
  13. 2018 High

    Defining the structural switch for full versus partial agonism: the ET-3- and IRL1620-bound crystal structures showed that full agonism requires disruption of the W6.48–D2.50 water-mediated hydrogen bond network, which partial agonists preserve.

    Evidence X-ray crystallography with IP accumulation assays

    PMID:30413709

    Open questions at the time
    • Dynamics of water network disruption during activation were not captured
    • How partial agonism translates to biased signaling profiles was not explored
  14. 2019 High

    Completing the transcriptional circuit: GATA2, SOX10, and NKX2.5 were shown to directly regulate EDNRB transcription, and EDNRB and RET reciprocally feed back on these shared transcription factors, providing the molecular explanation for RET–EDNRB epistasis in Hirschsprung disease.

    Evidence Chromatin immunoprecipitation and transactivation assays in human and mouse cellular/animal models

    PMID:31313802

    Open questions at the time
    • Quantitative dose–response relationship of the feedback loop was not modeled
    • Whether additional transcription factors contribute in specific ENS progenitor subtypes is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the active-state structure of EDNRB in complex with a G-protein or β-arrestin, the identity of kinases mediating rapid EDNRB phosphorylation and desensitization, the mechanistic basis for tissue-specific engagement of NOS1 versus eNOS, and the functional consequences of EDNRB promoter methylation in cancer progression in vivo.
  • No active-state GPCR–transducer complex structure available
  • Kinases for agonist-induced EDNRB phosphorylation unidentified
  • In vivo cancer consequences of EDNRB methylation not causally tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 5 R-HSA-382551 Transport of small molecules 4 R-HSA-1643685 Disease 3
Partners
AGTR1DRD3GATA2NHE3NKX2.5RETSOX10ZEB2

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 Crystal structure of human EDNRB in ligand-free form and in complex with endothelin-1 revealed that transmembrane helices 1, 2, 6, and 7 move to envelop the entire endothelin peptide in a virtually irreversible manner; agonist-induced conformational changes propagate to the G-protein coupling interface and induce flexibility in TM6, elucidating the activation mechanism and isopeptide selectivity between ET-1 and ET-3. X-ray crystallography with mutation analysis Nature High 27595334
2017 Crystal structures of human EDNRB bound to clinical antagonist bosentan and ETB-selective analog K-8794 showed that bosentan sterically prevents the inward movement of TM6, exerting antagonistic activity; the K-8794-bound structure revealed water-mediated hydrogen-bonding network at the transmembrane core and weak negative allosteric modulation by Na+ ions. X-ray crystallography (3.6 Å and 2.2 Å resolution) Nature structural & molecular biology High 28805809
2018 Crystal structures of human EDNRB in complex with ET-3 and the partial agonist IRL1620 revealed that disruption of water-mediated interactions between W6.48 and D2.50 is critical for full receptor activation; IRL1620 preserves these hydrogen-bonding interactions partially, explaining its partial agonistic effect. X-ray crystallography with functional analysis (IP accumulation assays) Nature communications High 30413709
2020 Crystal structure of human EDNRB in complex with sarafotoxin S6b at 3.0 Å resolution revealed the binding mode of an endothelin-like peptide and, combined with molecular dynamics simulations, provided structural insight into sarafotoxin subtype selectivity. X-ray crystallography and molecular dynamics simulations Biochemical and biophysical research communications High 32001000
1995 EDNRB on vascular smooth muscle cells mediates vasoconstriction in human resistance (forearm) and capacitance (hand vein) vessels in vivo, demonstrated using selective ETB agonists endothelin-3 and sarafotoxin S6c by intra-arterial infusion. In vivo pharmacology (intra-arterial infusion of selective agonists in humans) Circulation High 7634449
1992 EDNRB activation mediates both vasodilation (transient, endothelium-dependent) and vasoconstriction (sustained) in vivo, demonstrated using the selective ETB agonist sarafotoxin S6c in rats. In vivo pharmacology (selective ETB agonist administration in rats) Biochemical and biophysical research communications High 1323294
2000 EDNRB activation in the thick ascending limb of the loop of Henle decreases NaCl (chloride) flux by stimulating NO release through an intracellular calcium-dependent mechanism; this effect is blocked by the ETB antagonist BQ-788 and the NOS inhibitor L-NAME, but not by the ETA antagonist BQ-610. Isolated tubule perfusion assay with selective antagonists and NOS inhibitors American journal of physiology. Renal physiology High 10919853
2008 Renal medullary EDNRB activation induces diuresis and natriuresis through a NOS1 → cGMP → PKG signaling pathway; effects absent in ETB receptor-deficient rats and blocked by selective NOS1 inhibition or PKG inhibition. In vivo renal medullary infusion in anesthetized rats, ETB-deficient rat model, selective pharmacological inhibitors American journal of physiology. Renal physiology High 18305094
1999 EDNRB activation leads to phosphorylation and activation of the Na+/H+ exchanger isoform 3 (NHE3) on multiple threonine and serine residues, with this phosphorylation being ETB receptor-specific (not mediated by ETA) and correlating with increased antiporter activity. Overexpression of ETB in OKP cells, immunoprecipitation, alkaline phosphatase treatment, amiloride-sensitive transport assay The American journal of physiology High 10199826
1996 EDNRB activation increases NHE3 activity via two parallel pathways: a Ca2+-dependent pathway (50%) and a tyrosine kinase pathway (50%) involving cytoskeletal focal adhesion proteins (paxillin, p125FAK) and a membrane-associated p210 tyrosine kinase; disruption of focal adhesions by cytochalasin D blocks focal adhesion protein phosphorylation but not antiporter activation, implicating p210 in the tyrosine kinase pathway. Pharmacological inhibitors in OKP cells stably expressing ETB, immunoprecipitation of phosphoproteins The American journal of physiology High 8843705
1997 EDNRB undergoes rapid ligand-induced phosphorylation (within 5 min) leading to fast desensitization (>80% activity lost within 5 min), whereas ETA does not undergo ligand-induced phosphorylation and shows sustained activation; receptor internalization kinetics are identical for both subtypes, suggesting phosphorylation-dependent and internalization-independent desensitization mechanisms for EDNRB. Inositol phosphate accumulation assay, receptor phosphorylation assay, internalization assay in HEK cells expressing human receptors Biochemistry High 9341224
1992 EDNRB activation in rat glomeruli increases cGMP production via an L-arginine/nitric oxide-dependent mechanism that activates soluble guanylate cyclase; the ETA-selective antagonist BQ-123 has no effect, confirming ETB mediation. Glomerular cGMP accumulation assay with L-NNA, methylene blue, L-arginine, BQ-123, extracellular Ca2+ chelation The American journal of physiology High 1336308
1995 EDNRB activation promotes proliferation and migration of endothelial cells (bovine adrenal capillary and human umbilical vein endothelial cells) via an autocrine mechanism; the ETB-selective full agonist ET-(16-21) mimics the effect, and the ETB antagonist IRL-1038 blocks ET-3-induced and ET-(16-21)-induced migration, whereas the ETA antagonist BQ-123 is not effective. DNA synthesis, cell counting, cell migration assays with selective agonists and antagonists The American journal of physiology High 7653633
2008 EDNRB on pulmonary vascular endothelium mediates ET-1-induced impairment of alveolar fluid reabsorption via NO generation (cGMP-independent) leading to down-regulation of alveolar epithelial Na,K-ATPase activity and plasma membrane abundance; this requires endothelial-epithelial cell interaction and does not occur through direct action of ET-1 on alveolar epithelial cells. Isolated perfused rat lung, ETB-deficient transgenic rats, endothelial-epithelial co-culture, 86Rb+ uptake (Na,K-ATPase assay), L-NAME and guanylate cyclase inhibitor pharmacology American journal of respiratory and critical care medicine High 18948426
1999 Genetic and pharmacological disruption of EDNRB increases basal arterial blood pressure in mice by approximately 20 mmHg; the depressor effect of endogenous ET via EDNRB under basal conditions is partly mediated by prostacyclin (blocked by indomethacin) rather than nitric oxide. ETB gene-targeted mice (ETB-/s), ETB antagonist BQ-788, indomethacin, L-NMMA, ETA antagonist BQ-123 The American journal of physiology High 10198387
1993 EDNRB is localized by immunohistochemistry primarily to vascular endothelium in kidney, adrenal gland, lung, cerebellum, and pituitary gland; tissue distribution varies (lung ~70% ETB, testis <2% ETB), established using a subtype-specific antiserum that immunoprecipitates only ETB. Subtype-specific rabbit antiserum, Western blot, immunoprecipitation, immunohistochemistry The American journal of physiology High 8476120
1995 Active-site mutagenesis of ETB (Asp147Ala in TM2) abolishes ET-1 and ET-3 activation of phospholipase C without altering ligand binding affinity, demonstrating that Asp147 is required for transmembrane signal transduction but not for ligand recognition in EDNRB. Site-directed mutagenesis of human ETB expressed in COS cells, inositol phosphate accumulation assay, radioligand binding FEBS letters High 7698331
2002 Genetic epistasis between RET and EDNRB in Hirschsprung disease was demonstrated by non-complementation of aganglionosis in mouse intercrosses between Ret null and Ednrb hypomorphic piebald alleles, placing EDNRB in a gene interaction network with RET during enteric nervous system development. Genome-wide association in Mennonite trios, mouse intercross genetic epistasis analysis Nature genetics High 12355085
2019 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 common regulators, and these TFs are in turn controlled by EDNRB and RET in a dose-dependent feedback manner, explaining the mechanistic basis for RET-EDNRB epistasis in Hirschsprung disease. Chromatin immunoprecipitation, transactivation assays, human and mouse cellular models, animal models Human molecular genetics High 31313802
2017 SOX10 and ZEB2 transcription factors directly activate the EDNRB promoter, and two copies of Zeb2 are required for EDN3/EDNRB signaling to prevent neuronal differentiation of enteric progenitor cells; overexpression of EDNRB in Zeb2-heterozygous EPCs rescues the inhibition of neuronal differentiation, placing EDNRB downstream of SOX10/ZEB2 transcriptional control. Transactivation assays, ChIP, retroviral EDNRB overexpression in enteric progenitor cell cultures, mouse double mutant analysis Gastroenterology High 28063956
2006 EDNRB genetically interacts with Sox10 and Edn3 during enteric nervous system and melanocyte development; double mutant (Sox10;Ednrb) mice show more severe aganglionosis and melanocyte defects than single mutants, with increased apoptosis in vagal neural crest cells outside the gut but no increase in cell proliferation or differentiation defects within the stomach. Genetic mouse double-mutant phenotypic analysis, apoptosis and proliferation assays, immunohistochemistry Developmental biology High 16650841
2000 Big endothelin-1-induced diuresis and natriuresis are mediated mainly by EDNRB activation coupled to nitric oxide production; selective ETB antagonist A-192621.1 abolished these renal excretory responses, and effects were similarly blocked by L-NAME (NOS inhibitor). In vivo anesthetized rat pharmacology with selective ETB antagonist and NOS inhibitor Hypertension High 10720587
1997 Mouse EDNRB with a proline mutation in the fifth transmembrane domain causes a recessive lethal phenotype (white coat, megacolon), identifying this transmembrane proline as critical for EDNRB function in neural crest-derived melanocyte and enteric neuron development. Molecular characterization of induced alleles in mice (radiation/chemical mutagenesis), sequencing, Northern blot Proceedings of the National Academy of Sciences of the United States of America High 9371807
2015 EDNRB activation mediates vasogenic edema formation after status epilepticus via eNOS-mediated MMP-9 activation leading to ZO-1 tight junction protein degradation in endothelial cells; BQ788 (ETB antagonist) attenuates SE-induced vasogenic edema by inhibiting this eNOS/MMP-9/ZO-1 axis. Rat SE model, ETB antagonist BQ788, western blot for eNOS/MMP-9/ZO-1, BBB permeability assay Neuroscience Medium 26232046
2005 AT1 receptors physically interact with EDNRB (co-immunoprecipitation) in renal proximal tubule cells and regulate ETB receptor expression and surface membrane localization; angiotensin II via AT1 receptors increases ETB receptor expression in WKY but not SHR cells, and this impaired interaction may contribute to hypertension in SHRs. Immunoblotting, confocal colocalization, co-immunoprecipitation, cell surface membrane fractionation in immortalized RPT cells Hypertension Medium 16144989
2005 EDNRB activation decreases AT1 receptor protein expression in renal proximal tubule cells via direct receptor interaction (co-immunoprecipitation); ETB receptor agonist BQ3020 also increased AT1 receptor phosphorylation in WKY but decreased it in SHR cells, demonstrating aberrant ETB-AT1 cross-regulation in hypertension. Co-immunoprecipitation, immunoblotting, receptor phosphorylation in immortalized RPT cells from WKY and SHR Kidney international Medium 16014039
2009 D3 dopamine receptors physically interact with EDNRB (co-immunoprecipitation) in renal proximal tubule cells; D3 receptor activation increases ETB receptor expression and augments ETB-mediated inhibition of Na+/K+-ATPase in WKY cells, but this regulation is impaired in SHR cells where D3/ETB co-immunoprecipitation is markedly reduced. Co-immunoprecipitation, immunoblotting, Na+/K+-ATPase activity assay in RPT cells American journal of hypertension Medium 19390510
2008 ET-1-mediated apoptosis of retinal ganglion cells (RGC-5 cells) is mediated by EDNRB, involving cytochrome c release, JNK phosphorylation, and upregulation of ETB receptor expression; this was confirmed in ETB receptor-deficient rats where ET-1-induced apoptosis was markedly attenuated. ETB-deficient rat model, flow cytometry, cytochrome c western blot, JNK phosphorylation, ETB antagonist BQ788 Canadian journal of physiology and pharmacology Medium 18516102
2001 EDNRB promoter CpG island methylation silences gene expression; treatment with 5-aza-2'-deoxycytidine restores all four EDNRB transcripts, and a low-methylation region immediately 5' to the transcription start site correlates with expression of the proximal transcript, while downstream methylation does not block initiation. Bisulfite sequencing, 5-aza-2'-deoxycytidine treatment, RT-PCR expression analysis in normal and tumor cells Human molecular genetics Medium 11309363
2017 EDN3/EDNRB signaling is required for melanocyte stem cell (McSC) activation and regeneration of follicular and epidermal melanocytes after epilation; genetic and pharmacological disruption of EDNRB significantly blocks epilation-induced melanocyte regeneration and skin/hair hyperpigmentation, with EDN3 upregulation occurring in the dermal papilla and epidermis after epilation. Genetic EDNRB disruption and pharmacological blockade in mice, immunohistochemistry Scientific reports Medium 28779103
2001 ETB receptor activation inhibits platelet aggregation ex vivo in mice via ETB-dependent prostacyclin generation (COX-2 pathway); BQ-788 (ETB antagonist) abolishes this inhibitory effect, and indomethacin or tranylcypromine (prostacyclin synthase inhibitor) markedly reduces it. Ex vivo platelet aggregation assay in mice, selective ETB agonist IRL-1620, antagonist BQ-788, cyclooxygenase inhibitors British journal of pharmacology Medium 11181435
2013 Neural crest cell-specific deletion of Ednrb in mice results in decreased neuronal density and altered neurotransmitter expression (increased nNOS and VIP, decreased ChAT) in the ganglionated colon proximal to the aganglionic region, demonstrating that EDNRB function in neural crest cells is required for normal enteric nervous system organization. Neural crest cell-specific conditional Ednrb knockout mice, immunohistochemistry, neuronal counting Neurogastroenterology and motility Medium 23360229

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 471 8124808
1992 The endothelin ETB receptor mediates both vasodilation and vasoconstriction in vivo. Biochemical and biophysical research communications 395 1323294
1992 Endothelin ETA and ETB receptors mediate vascular smooth muscle contraction. British journal of pharmacology 279 1472978
1992 A potent and specific agonist, Suc-[Glu9,Ala11,15]-endothelin-1(8-21), IRL 1620, for the ETB receptor. Biochemical and biophysical research communications 258 1315540
1995 Endothelin ETA and ETB receptors cause vasoconstriction of human resistance and capacitance vessels in vivo. Circulation 257 7634449
2007 Contrasting actions of endothelin ET(A) and ET(B) receptors in cardiovascular disease. Annual review of pharmacology and toxicology 241 17002597
2002 Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease. Nature genetics 216 12355085
1996 Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. Human molecular genetics 173 8852660
2016 Activation mechanism of endothelin ETB receptor by endothelin-1. Nature 128 27595334
2000 Endothelin inhibits thick ascending limb chloride flux via ET(B) receptor-mediated NO release. American journal of physiology. Renal physiology 114 10919853
1995 Proliferation and migration of endothelial cells is promoted by endothelins via activation of ETB receptors. The American journal of physiology 106 7653633
2006 Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte development. Developmental biology 105 16650841
2004 Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis in the Sox10Dom mouse model of Hirschsprung disease. Human molecular genetics 93 15294878
2001 The endothelin receptor B (EDNRB) promoter displays heterogeneous, site specific methylation patterns in normal and tumor cells. Human molecular genetics 88 11309363
2010 KIF1A and EDNRB are differentially methylated in primary HNSCC and salivary rinses. International journal of cancer 80 20162572
2001 EDNRB/EDN3 and Hirschsprung disease type II. Pigment cell research 80 11434563
1995 Effects of separate and combined ETA and ETB blockade on ET-1-induced constriction in perfused rat lungs. The American journal of physiology 80 7491987
2005 ETA and ETB receptors differentially modulate afferent and efferent arteriolar responses to endothelin. British journal of pharmacology 77 16231007
1999 ETB receptor activation leads to activation and phosphorylation of NHE3. The American journal of physiology 77 10199826
2006 Distribution of endothelin receptor subtypes ETA and ETB in the rat kidney. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 76 16835394
2017 Endothelin ETA Receptor Blockade, by Activating ETB Receptors, Increases Vascular Permeability and Induces Exaggerated Fluid Retention. The Journal of pharmacology and experimental therapeutics 73 28223322
2017 X-ray structures of endothelin ETB receptor bound to clinical antagonist bosentan and its analog. Nature structural & molecular biology 69 28805809
2005 Evaluation of the RET regulatory landscape reveals the biological relevance of a HSCR-implicated enhancer. Human molecular genetics 67 16269442
1996 An orally active ETA/ETB receptor antagonist ameliorates proteinuria and glomerular lesions in rats with proliferative nephritis. Kidney international 67 8872972
2018 Crystal structures of human ETB receptor provide mechanistic insight into receptor activation and partial activation. Nature communications 65 30413709
1999 Elevation of blood pressure by genetic and pharmacological disruption of the ETB receptor in mice. The American journal of physiology 65 10198387
2008 Renal medullary ETB receptors produce diuresis and natriuresis via NOS1. American journal of physiology. Renal physiology 64 18305094
2003 Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR). Human molecular genetics 63 14600022
2018 News from the endothelin-3/EDNRB signaling pathway: Role during enteric nervous system development and involvement in neural crest-associated disorders. Developmental biology 61 30171849
1997 Endothelin-1 stimulates steroid secretion of human adrenocortical cells ex vivo via both ETA and ETB receptor subtypes. The Journal of clinical endocrinology and metabolism 60 9329384
1996 Role of tyrosine kinase pathways in ETB receptor activation of NHE3. The American journal of physiology 56 8843705
1995 Are there different ETB receptors mediating constriction and relaxation? Journal of cardiovascular pharmacology 56 8587383
1993 Immunochemical characterization and localization of endothelin ETB receptor. The American journal of physiology 56 8476120
2007 Cerebrovascular ETB, 5-HT1B, and AT1 receptor upregulation correlates with reduction in regional CBF after subarachnoid hemorrhage. American journal of physiology. Heart and circulatory physiology 55 17873013
2001 Analysis of the RET, GDNF, EDN3, and EDNRB genes in patients with intestinal neuronal dysplasia and Hirschsprung disease. Gut 55 11302967
2002 Promoter hypermethylation of the EDNRB gene in nasopharyngeal carcinoma. International journal of cancer 54 11920632
2008 Role of the ETB receptor in retinal ganglion cell death in glaucoma. Canadian journal of physiology and pharmacology 53 18516102
1997 Subtype-specific desensitization of human endothelin ETA and ETB receptors reflects differential receptor phosphorylation. Biochemistry 52 9341224
2013 Hypermethylation of EDNRB promoter contributes to the risk of colorectal cancer. Diagnostic pathology 51 24326135
2006 MEK1/2 inhibition attenuates vascular ETA and ETB receptor alterations after cerebral ischaemia. Experimental brain research 50 17091294
2015 ETB receptor-mediated MMP-9 activation induces vasogenic edema via ZO-1 protein degradation following status epilepticus. Neuroscience 49 26232046
2000 Mechanisms of big endothelin-1-induced diuresis and natriuresis : role of ET(B) receptors. Hypertension (Dallas, Tex. : 1979) 49 10720587
1995 ETA and ETB endothelin receptors in human myometrium characterized by the subtype selective ligands BQ123, BQ3020, FR139317 and PD151242. The Journal of endocrinology 48 7891013
2013 Altered neuronal density and neurotransmitter expression in the ganglionated region of Ednrb null mice: implications for Hirschsprung's disease. Neurogastroenterology and motility 46 23360229
2010 New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease. Genetics in medicine : official journal of the American College of Medical Genetics 44 20009762
1996 Localization of endothelin ETA and ETB receptor-mediated constriction in the renal microcirculation of rats. The Journal of physiology 44 8951723
2012 Genome-wide copy number analysis uncovers a new HSCR gene: NRG3. PLoS genetics 43 22589734
2017 ETB receptor contribution to vascular dysfunction in postmenopausal women. American journal of physiology. Regulatory, integrative and comparative physiology 42 28438762
1995 Functional role of endothelin ETA and ETB receptors in venous and arterial smooth muscle. European journal of pharmacology 41 8991802
2010 Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations. Nature structural & molecular biology 40 20473317
2008 Targeting endothelin ETA and ETB receptors inhibits antigen-induced neutrophil migration and mechanical hypernociception in mice. Naunyn-Schmiedeberg's archives of pharmacology 39 18854982
2006 Aberrant methylation of EDNRB and p16 genes in hepatocellular carcinoma (HCC) in Taiwan. Oncology reports 39 16391877
2002 BQ-788, a selective endothelin ET(B) receptor antagonist. Cardiovascular drug reviews 38 12070534
1995 ETB and epidermal growth factor receptor stimulation of wound closure in bovine corneal epithelial cells. Investigative ophthalmology & visual science 38 7499084
1992 Activation of endothelin ETB receptors increases glomerular cGMP via an L-arginine-dependent pathway. The American journal of physiology 38 1336308
2018 The effect of miR-124-3p on cell proliferation and apoptosis in bladder cancer by targeting EDNRB. Archives of medical science : AMS 37 31572460
2008 Endothelin-1 impairs alveolar epithelial function via endothelial ETB receptor. American journal of respiratory and critical care medicine 37 18948426
1993 Two subtypes of the endothelin receptor (ETA and ETB) mediate vasoconstriction in the perfused rat heart. Journal of cardiovascular pharmacology 37 7509957
1996 Decreased ET(B) receptor expression in human metastatic melanoma cells. Biochemical and biophysical research communications 36 8645250
1993 Altered expression of ETB-receptor mRNA in the lung of rats with pulmonary hypertension. Journal of cardiovascular pharmacology 36 7509980
2011 Quantitative analysis of promoter methylation of the EDNRB gene in gastric cancer. Medical oncology (Northwood, London, England) 34 21264540
1995 Aspartate mutation distinguishes ETA but not ETB receptor subtype-selective ligand binding while abolishing phospholipase C activation in both receptors. FEBS letters 34 7698331
2017 Epilation induces hair and skin pigmentation through an EDN3/EDNRB-dependent regenerative response of melanocyte stem cells. Scientific reports 33 28779103
2008 Polymorphisms of EDNRB, ATG, and ACE genes in salt-sensitive hypertension. Canadian journal of physiology and pharmacology 33 18758497
2003 ACE inhibition increases expression of the ETB receptor in kidneys of mice with unilateral obstruction. American journal of physiology. Renal physiology 33 12473537
2002 ABCD syndrome is caused by a homozygous mutation in the EDNRB gene. American journal of medical genetics 32 11891690
2009 D3 dopamine receptor regulation of ETB receptors in renal proximal tubule cells from WKY and SHRs. American journal of hypertension 30 19390510
1994 Divergent expression of EtA and EtB receptors in response to cyclosporine in mesangial cells. The American journal of pathology 30 8129032
2017 Differentiation of Mouse Enteric Nervous System Progenitor Cells Is Controlled by Endothelin 3 and Requires Regulation of Ednrb by SOX10 and ZEB2. Gastroenterology 29 28063956
2011 Genetic background strongly modifies the severity of symptoms of Hirschsprung disease, but not hearing loss in rats carrying Ednrb(sl) mutations. PloS one 29 21915282
2022 BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids. Cell death discovery 28 35110536
2021 Endothelin ETB Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders. International journal of molecular sciences 28 33919338
2017 Adamdec1, Ednrb and Ptgs1/Cox1, inflammation genes upregulated in the intestinal mucosa of obese rats, are downregulated by three probiotic strains. Scientific reports 28 28512356
2003 Unique endothelin receptor binding in kidneys of ETB receptor deficient rats. American journal of physiology. Regulatory, integrative and comparative physiology 28 12611392
1994 Effects of selective ETB-receptor stimulation on arterial, venous and capillary functions in cat skeletal muscle. British journal of pharmacology 28 7921617
2019 A gene regulatory network explains RET-EDNRB epistasis in Hirschsprung disease. Human molecular genetics 27 31313802
2002 Expression of ET(A) and ET(B) receptor mRNA in human cerebral arteries. British journal of neurosurgery 27 12046734
2005 Altered AT1 receptor regulation of ETB receptors in renal proximal tubule cells of spontaneously hypertensive rats. Hypertension (Dallas, Tex. : 1979) 26 16144989
1997 Dual control of seminiferous tubule contractility mediated by ETA and ETB endothelin receptor subtypes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 9068617
1995 Identification and function of putative ETB receptor subtypes in the dog kidney. Journal of cardiovascular pharmacology 26 8587403
2017 LncRNA AFAP1-AS Functions as a Competing Endogenous RNA to Regulate RAP1B Expression by sponging miR-181a in the HSCR. International journal of medical sciences 25 28924375
2012 Sacral neural crest-derived cells enter the aganglionic colon of Ednrb-/- mice along extrinsic nerve fibers. The Journal of comparative neurology 25 21858821
2004 Role of endothelin ETB receptor in the pathogenesis of monocrotaline-induced pulmonary hypertension in rats. European journal of pharmacology 25 15359489
1994 Characterization of three non-peptide endothelin receptor ligands using human cloned ETA and ETB receptors. British journal of pharmacology 25 7952888
2021 ETB receptor-mediated vasodilation is regulated by estradiol in young women. American journal of physiology. Heart and circulatory physiology 24 34415188
2008 Identification of aberrant promoter methylation of EDNRB gene in esophageal squamous cell carcinoma. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus 24 18564167
2020 Role of endothelin receptor type B (EDNRB) in lung adenocarcinoma. Thoracic cancer 23 32394530
2013 Methylation analysis of EDNRB in human colon tissues of Hirschsprung's disease. Pediatric surgery international 23 23579558
2000 Loss of late primitive streak mesoderm and interruption of left-right morphogenesis in the Ednrb(s-1Acrg) mutant mouse. Developmental biology 22 10964471
1996 Contractile endothelin-B (ETB) receptors in human small bronchi. The European respiratory journal 22 8777976
2020 Altered endothelial ETB receptor expression in postmenopausal women. American journal of physiology. Heart and circulatory physiology 21 32559137
2019 Endothelins (EDN1, EDN2, EDN3) and their receptors (EDNRA, EDNRB, EDNRB2) in chickens: Functional analysis and tissue distribution. General and comparative endocrinology 21 31351053
2005 Aberrant ETB receptor regulation of AT receptors in immortalized renal proximal tubule cells of spontaneously hypertensive rats. Kidney international 21 16014039
1999 Characterization of an endothelin ET(B) receptor in the gill of the dogfish shark Squalus acanthias. The Journal of experimental biology 21 10574737
2020 Crystal structure of human endothelin ETB receptor in complex with sarafotoxin S6b. Biochemical and biophysical research communications 20 32001000
2017 TRPC3- and ETB receptor-mediated PI3K/AKT activation induces vasogenic edema formation following status epilepticus. Brain research 20 28764936
2014 Effect of SNP polymorphisms of EDN1, EDNRA, and EDNRB gene on ischemic stroke. Cell biochemistry and biophysics 20 24633486
1997 ET-1-induced bronchoconstriction is mediated via ETB receptor in mice. Journal of applied physiology (Bethesda, Md. : 1985) 20 9216943
2001 Role of ETB and B2 receptors in the ex vivo platelet inhibitory properties of endothelin and bradykinin in the mouse. British journal of pharmacology 19 11181435
1997 Molecular characterization of four induced alleles at the Ednrb locus. Proceedings of the National Academy of Sciences of the United States of America 19 9371807