Endothelin-3 (EDN3) encodes a secreted vasoactive and developmental peptide hormone synthesized as a 238-amino-acid preproprotein that is proteolytically cleaved by furin-like proprotein convertases into big endothelin-3 and subsequently converted by endothelin-converting enzymes (ECE-1, ECE-2) or the Kell metalloendopeptidase (KEL) into the mature 21-residue bicyclic peptide endothelin-3 (ET-3), stabilized by two intramolecular disulfide bonds (Cys1-Cys15 and Cys3-Cys11). Mature ET-3 acts in the extracellular space as a high-affinity agonist of the endothelin B receptor (EDNRB, equipotent with ET-1 and ET-2) and a lower-affinity agonist of the endothelin A receptor (EDNRA). Through Gq/11-coupled phospholipase C activation, IP3-mediated intracellular calcium mobilization, and MAPK signaling, EDN3-EDNRB signaling regulates systemic arterial blood pressure, vein smooth muscle contraction, and the proliferation, migration, and differentiation of enteric neural crest-derived precursors and melanoblasts; loss-of-function mutations in EDN3 cause Waardenburg syndrome type 4B and congenital central hypoventilation syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002690 positive regulation of leukocyte chemotaxis | IDA PMID:9696419 The involvement of protein kinase G in stimulation of neutro... | KEEP AS NON CORE | Summary: Downstream immunomodulatory effect of endothelin-3 stimulating human neutrophil migration via cGMP/protein kinase G signaling. Reason: Elferink and de Koster (PMID:9696419) demonstrated that nanomolar ET-3 stimulates human neutrophil migration via a guanylate cyclase and protein kinase G-dependent pathway; retained as a non-core downstream cellular response to endothelin receptor activation. Supporting Evidence: PMID:9696419 Activation of human neutrophil migration by endothelin-1 and endothelin-3 is inhibited by guanylate cyclase inhibitors, by antagonists of protein kinase G (G-kinase), and by KT-5823, an inhibitor of G-kinase. |
| GO:0003100 regulation of systemic arterial blood pressure by endothelin | IBA GO_REF:0000033 | ACCEPT | Summary: Core physiological role of endothelin-3 in regulating systemic arterial blood pressure. Reason: Synthetic human ET-3 elicits systemic pressor and hemodynamic responses in vivo via endothelin receptors (PMID:2649896). Supporting Evidence: PMID:2649896 Synthetic ET-1, ET-2, and ET-3 were prepared according to the deduced amino acid sequences, and the biological activities were assayed by contraction of isolated porcine coronary artery strips and by intravenous injection to anesthetized rats. All these synthetic peptides produced strong vasoconstrictor and pressor responses. |
| GO:0003100 regulation of systemic arterial blood pressure by endothelin | IDA PMID:2649896 The human endothelin family: three structurally and pharmaco... | ACCEPT | Summary: Core physiological role of endothelin-3 in regulating systemic arterial blood pressure. Reason: Synthetic human ET-3 elicits systemic pressor and hemodynamic responses in vivo via endothelin receptors (PMID:2649896). Supporting Evidence: PMID:2649896 Synthetic ET-1, ET-2, and ET-3 were prepared according to the deduced amino acid sequences, and the biological activities were assayed by contraction of isolated porcine coronary artery strips and by intravenous injection to anesthetized rats. All these synthetic peptides produced strong vasoconstrictor and pressor responses. |
| GO:0005102 signaling receptor binding | TAS PMID:8298278 Molecular interactions at the interface of Candida albicans ... | MODIFY | Summary: Broad signaling receptor binding annotation that should be refined to specific endothelin receptor binding terms. Reason: GO:0005102 (signaling receptor binding) is true but too general; ET-3 specifically binds EDNRB with high affinity (GO:0031708) and EDNRA with lower affinity (GO:0031707) (PMID:1713452, PMID:10770212). Proposed replacements: endothelin B receptor binding endothelin A receptor binding |
| GO:0005179 hormone activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function of mature endothelin-3 as a secreted vasoactive and developmental peptide hormone. Reason: Mature ET-3 is a 21-amino-acid secreted peptide hormone that signals through EDNRB and EDNRA to regulate vascular tone, endocrine secretion, and neural crest development (PMID:2649896, PMID:10770212). Supporting Evidence: PMID:2649896 Synthetic ET-1, ET-2, and ET-3 were prepared according to the deduced amino acid sequences, and the biological activities were assayed by contraction of isolated porcine coronary artery strips and by intravenous injection to anesthetized rats. All these synthetic peptides produced strong vasoconstrictor and pressor responses. |
| GO:0005179 hormone activity | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | ACCEPT | Summary: Core molecular function of mature endothelin-3 as a secreted vasoactive and developmental peptide hormone. Reason: Mature ET-3 is a 21-amino-acid secreted peptide hormone that signals through EDNRB and EDNRA to regulate vascular tone, endocrine secretion, and neural crest development (PMID:2649896, PMID:10770212). Supporting Evidence: PMID:2649896 Synthetic ET-1, ET-2, and ET-3 were prepared according to the deduced amino acid sequences, and the biological activities were assayed by contraction of isolated porcine coronary artery strips and by intravenous injection to anesthetized rats. All these synthetic peptides produced strong vasoconstrictor and pressor responses. |
| GO:0005179 hormone activity | IDA PMID:2649896 The human endothelin family: three structurally and pharmaco... | ACCEPT | Summary: Core molecular function of mature endothelin-3 as a secreted vasoactive and developmental peptide hormone. Reason: Mature ET-3 is a 21-amino-acid secreted peptide hormone that signals through EDNRB and EDNRA to regulate vascular tone, endocrine secretion, and neural crest development (PMID:2649896, PMID:10770212). Supporting Evidence: PMID:2649896 Synthetic ET-1, ET-2, and ET-3 were prepared according to the deduced amino acid sequences, and the biological activities were assayed by contraction of isolated porcine coronary artery strips and by intravenous injection to anesthetized rats. All these synthetic peptides produced strong vasoconstrictor and pressor responses. |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: Core extracellular localization where mature endothelin-3 is secreted and binds cell-surface receptors. Reason: Mature ET-3 is secreted into the extracellular space and blood plasma where it engages EDNRB and EDNRA on target cells (PMID:15691296, PMID:2649896). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | IDA PMID:15691296 Ursodeoxycholic acid reduces increased circulating endotheli... | ACCEPT | Summary: Core extracellular localization where mature endothelin-3 is secreted and binds cell-surface receptors. Reason: Mature ET-3 is secreted into the extracellular space and blood plasma where it engages EDNRB and EDNRA on target cells (PMID:15691296, PMID:2649896). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Core extracellular localization where mature endothelin-3 is secreted and binds cell-surface receptors. Reason: Mature ET-3 is secreted into the extracellular space and blood plasma where it engages EDNRB and EDNRA on target cells (PMID:15691296, PMID:2649896). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-379048 | ACCEPT | Summary: Core extracellular localization where mature endothelin-3 is secreted and binds cell-surface receptors. Reason: Mature ET-3 is secreted into the extracellular space and blood plasma where it engages EDNRB and EDNRA on target cells (PMID:15691296, PMID:2649896). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-388560 | ACCEPT | Summary: Core extracellular localization where mature endothelin-3 is secreted and binds cell-surface receptors. Reason: Mature ET-3 is secreted into the extracellular space and blood plasma where it engages EDNRB and EDNRA on target cells (PMID:15691296, PMID:2649896). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5694082 | ACCEPT | Summary: Core extracellular localization where mature endothelin-3 is secreted and binds cell-surface receptors. Reason: Mature ET-3 is secreted into the extracellular space and blood plasma where it engages EDNRB and EDNRA on target cells (PMID:15691296, PMID:2649896). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749448 | ACCEPT | Summary: Core extracellular localization where mature endothelin-3 is secreted and binds cell-surface receptors. Reason: Mature ET-3 is secreted into the extracellular space and blood plasma where it engages EDNRB and EDNRA on target cells (PMID:15691296, PMID:2649896). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749452 | ACCEPT | Summary: Core extracellular localization where mature endothelin-3 is secreted and binds cell-surface receptors. Reason: Mature ET-3 is secreted into the extracellular space and blood plasma where it engages EDNRB and EDNRA on target cells (PMID:15691296, PMID:2649896). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9731924 | ACCEPT | Summary: Core extracellular localization where mature endothelin-3 is secreted and binds cell-surface receptors. Reason: Mature ET-3 is secreted into the extracellular space and blood plasma where it engages EDNRB and EDNRA on target cells (PMID:15691296, PMID:2649896). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0006874 intracellular calcium ion homeostasis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Non-core intracellular calcium ion homeostasis annotation reflecting downstream GPCR-induced Ca2+ mobilization. Reason: Endothelin receptor activation triggers acute IP3-dependent intracellular Ca2+ release and cytosolic Ca2+ elevation (GO:0007204); retained as non-core downstream context. |
| GO:0007165 signal transduction | TAS PMID:8298278 Molecular interactions at the interface of Candida albicans ... | MODIFY | Summary: Broad signal transduction annotation that should be refined to endothelin receptor signaling pathway. Reason: GO:0007165 (signal transduction) is true but overly general; ET-3 specifically initiates the endothelin receptor signaling pathway (GO:0086100) and phospholipase C-activating endothelin receptor signaling pathway (GO:0160135) (PMID:1713452, PMID:1917960). |
| GO:0007166 cell surface receptor signaling pathway | IDA PMID:1713452 Cloning and functional expression of human cDNA for the ETB ... | MODIFY | Summary: Broad cell surface receptor signaling pathway annotation that should be refined to endothelin receptor signaling pathway. Reason: GO:0007166 (cell surface receptor signaling pathway) is true but overly general; ET-3 specifically initiates the endothelin receptor signaling pathway (GO:0086100) and phospholipase C-activating endothelin receptor signaling pathway (GO:0160135) (PMID:1713452, PMID:1917960). |
| GO:0007267 cell-cell signaling | TAS PMID:8298278 Molecular interactions at the interface of Candida albicans ... | MODIFY | Summary: Broad cell-cell signaling annotation that should be refined to endothelin receptor signaling pathway. Reason: GO:0007267 (cell-cell signaling) is true but overly general; ET-3 specifically initiates the endothelin receptor signaling pathway (GO:0086100) and phospholipase C-activating endothelin receptor signaling pathway (GO:0160135) (PMID:1713452, PMID:1917960). |
| GO:0007411 axon guidance | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Non-core developmental role of endothelin-3/EDNRB signaling in guiding sympathetic and enteric neural crest axonal projections. Reason: Transferred by Ensembl Compara orthology from mouse Edn3, where locally secreted ET-3 acts through EDNRB to guide developing sympathetic and enteric neuron projections; retained as a non-core downstream developmental outcome of EDNRB signaling. |
| GO:0008015 blood circulation | TAS PMID:8298278 Molecular interactions at the interface of Candida albicans ... | MODIFY | Summary: Broad blood circulation annotation that should be refined to endothelin blood pressure regulation and vasoconstriction. Reason: GO:0008015 (blood circulation) is true but less specific than GO:0003100 (regulation of systemic arterial blood pressure by endothelin) and GO:0042310 (vasoconstriction), both already supported for EDN3 (PMID:2649896, PMID:8982507). Proposed replacements: regulation of systemic arterial blood pressure by endothelin vasoconstriction |
| GO:0008284 positive regulation of cell population proliferation | IDA PMID:22897442 Apolipoprotein B is a new target of the GDNF/RET and ET-3/ED... | ACCEPT | Summary: Core developmental and mitogenic role of endothelin-3 in stimulating progenitor and target cell proliferation. Reason: ET-3 stimulates proliferation of enteric nervous system neural crest progenitors, melanocytes, and GnRH-secreting neuroblasts via EDNRB/EDNRA signaling (PMID:22897442, PMID:1917960, PMID:10770212). Supporting Evidence: PMID:1917960 Upon incubation with cultured cells, the mass contents of inositol 1,4,5-trisphosphate and intracellular calcium level were substantially increased by 10 nM ET-1, ET-2, and ET-3, but not by big-ET with maximal response at 80-130-s postincubation. |
| GO:0010460 positive regulation of heart rate | IDA PMID:2649896 The human endothelin family: three structurally and pharmaco... | KEEP AS NON CORE | Summary: Downstream cardiovascular chronotropic response to systemic endothelin-3 administration in vivo. Reason: Intravenous bolus administration of synthetic ET-3 in anesthetized rats (PMID:2649896) evokes a biphasic hemodynamic response accompanied by reflex and direct chronotropic effects; retained as a non-core organismal cardiovascular phenotype downstream of endothelin receptor signaling. |
| GO:0010468 regulation of gene expression | IGI PMID:22897442 Apolipoprotein B is a new target of the GDNF/RET and ET-3/ED... | KEEP AS NON CORE | Summary: Downstream transcriptional regulation in enteric neural crest progenitors mediated by ET-3/EDNRB and GDNF/RET signaling. Reason: As an extracellular peptide hormone, ET-3 acts upstream of transcriptional target genes (such as Apob in enteric neural crest progenitors, PMID:22897442) via EDNRB signaling; retained as a non-core downstream signaling outcome. Supporting Evidence: PMID:22897442 GDNF/RET and Endothelin-3 (ET-3)/EDNRB regulate survival, differentiation, migration, and proliferation of neural crest-derived cells. |
| GO:0014824 artery smooth muscle contraction | IDA NOT PMID:8982507 Characterization of endothelin receptors in the human umbili... | KEEP AS NON CORE | Summary: Informative negative experimental finding showing that ET-3 does not contract human umbilical artery smooth muscle where EDNRA predominates. Reason: PMID:8982507 demonstrated that whereas ET-1 and ET-2 potently contract human umbilical artery via EDNRA, ET-3 (up to 100 nM) is inactive in umbilical artery while contracting umbilical vein via EDNRB. Supporting Evidence: PMID:8982507 Endothelin-1 (ET-1) and endothelin-2 (ET-2) are potent stimulants of both the human umbilical artery (pEC50 7.9 and 7.5) and vein (pEC50 8.1 and 8.0). Endothelin-3 (ET-3) is inactive on the artery but contracts the vein (pEC50 7.6). |
| GO:0014826 vein smooth muscle contraction | IBA GO_REF:0000033 | ACCEPT | Summary: Core vascular smooth muscle response to endothelin-3 in human veins. Reason: ET-3 potently contracts isolated human umbilical vein smooth muscle via EDNRB activation with an EC50 of 27.6 nM (PMID:8982507). Supporting Evidence: PMID:8982507 Endothelin-1 (ET-1) and endothelin-2 (ET-2) are potent stimulants of both the human umbilical artery (pEC50 7.9 and 7.5) and vein (pEC50 8.1 and 8.0). Endothelin-3 (ET-3) is inactive on the artery but contracts the vein (pEC50 7.6). |
| GO:0014826 vein smooth muscle contraction | IDA PMID:8982507 Characterization of endothelin receptors in the human umbili... | ACCEPT | Summary: Core vascular smooth muscle response to endothelin-3 in human veins. Reason: ET-3 potently contracts isolated human umbilical vein smooth muscle via EDNRB activation with an EC50 of 27.6 nM (PMID:8982507). Supporting Evidence: PMID:8982507 Endothelin-1 (ET-1) and endothelin-2 (ET-2) are potent stimulants of both the human umbilical artery (pEC50 7.9 and 7.5) and vein (pEC50 8.1 and 8.0). Endothelin-3 (ET-3) is inactive on the artery but contracts the vein (pEC50 7.6). |
| GO:0019229 regulation of vasoconstriction | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping to regulation of vasoconstriction that should be replaced by direct vasoconstriction and endothelin-mediated blood pressure regulation. Reason: InterPro2GO maps the endothelin signature (IPR001928/IPR019764) to GO:0019229 (regulation of vasoconstriction), whereas mature ET-3 directly evokes vasoconstriction (GO:0042310) and regulates systemic arterial blood pressure (GO:0003100) via endothelin receptors (PMID:2649896, PMID:8982507). Proposed replacements: regulation of systemic arterial blood pressure by endothelin vasoconstriction |
| GO:0030072 peptide hormone secretion | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | MODIFY | Summary: Role of endothelin-3 in stimulating GnRH peptide hormone secretion behaves as positive regulation rather than executing exocytosis. Reason: In PMID:10770212, exogenous ET-3 stimulates GnRH release from FNC-B4 neurons via endothelin receptors; as an extracellular signaling ligand, EDN3 positively regulates peptide hormone secretion (GO:0090277 / GO:0046887) rather than forming the secretory machinery itself. Proposed replacements: positive regulation of hormone secretion |
| GO:0030593 neutrophil chemotaxis | IDA PMID:9696419 The involvement of protein kinase G in stimulation of neutro... | KEEP AS NON CORE | Summary: Downstream immunomodulatory response where exogenous endothelin-3 stimulates human neutrophil chemotactic migration. Reason: Elferink and de Koster (PMID:9696419) showed that nanomolar ET-3 stimulates human neutrophil chemotaxis via a cGMP/protein kinase G-dependent mechanism; retained as a non-core cell-type-specific response downstream of endothelin receptor signaling. Supporting Evidence: PMID:9696419 Activation of human neutrophil migration by endothelin-1 and endothelin-3 is inhibited by guanylate cyclase inhibitors, by antagonists of protein kinase G (G-kinase), and by KT-5823, an inhibitor of G-kinase. |
| GO:0031175 neuron projection development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Non-core developmental role of endothelin-3/EDNRB signaling in enteric and sympathetic neuron projection development. Reason: Transferred by Ensembl Compara orthology from mouse Edn3, reflecting the role of ET-3/EDNRB signaling in promoting neurite outgrowth and projection development of neural crest-derived neurons; retained as a non-core developmental context. |
| GO:0031708 endothelin B receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function of endothelin-3 as a high-affinity ligand for the endothelin B receptor (EDNRB). Reason: Radioligand competition and functional Ca2+ assays on cloned human EDNRB demonstrate that ET-3 binds EDNRB with high affinity equipotent to ET-1 and ET-2 (PMID:1713452). Supporting Evidence: PMID:1713452 COS cells transiently transfected with the cloned cDNA expressed specific, high-affinity binding sites for endothelin isopeptides and responded to the peptides with a transient increase of [Ca2+]i; endothelin-1 and endothelin-3 exhibited approximately equal potencies both in displacing 125I-labeled endothelin-1 binding and in eliciting [Ca2+]i transients. |
| GO:0031708 endothelin B receptor binding | IPI PMID:1713452 Cloning and functional expression of human cDNA for the ETB ... | ACCEPT | Summary: Core molecular function of endothelin-3 as a high-affinity ligand for the endothelin B receptor (EDNRB). Reason: Radioligand competition and functional Ca2+ assays on cloned human EDNRB demonstrate that ET-3 binds EDNRB with high affinity equipotent to ET-1 and ET-2 (PMID:1713452). Supporting Evidence: PMID:1713452 COS cells transiently transfected with the cloned cDNA expressed specific, high-affinity binding sites for endothelin isopeptides and responded to the peptides with a transient increase of [Ca2+]i; endothelin-1 and endothelin-3 exhibited approximately equal potencies both in displacing 125I-labeled endothelin-1 binding and in eliciting [Ca2+]i transients. |
| GO:0042310 vasoconstriction | IDA PMID:2649896 The human endothelin family: three structurally and pharmaco... | ACCEPT | Summary: Core physiological effect of endothelin-3 on vascular smooth muscle constriction. Reason: ET-3 induces vasoconstriction in vascular beds expressing functional EDNRB, such as human umbilical vein, and evokes systemic vasoconstrictor responses (PMID:2649896, PMID:8982507). Supporting Evidence: PMID:8982507 Endothelin-1 (ET-1) and endothelin-2 (ET-2) are potent stimulants of both the human umbilical artery (pEC50 7.9 and 7.5) and vein (pEC50 8.1 and 8.0). Endothelin-3 (ET-3) is inactive on the artery but contracts the vein (pEC50 7.6). |
| GO:0042310 vasoconstriction | IDA PMID:8982507 Characterization of endothelin receptors in the human umbili... | ACCEPT | Summary: Core physiological effect of endothelin-3 on vascular smooth muscle constriction. Reason: ET-3 induces vasoconstriction in vascular beds expressing functional EDNRB, such as human umbilical vein, and evokes systemic vasoconstrictor responses (PMID:2649896, PMID:8982507). Supporting Evidence: PMID:8982507 Endothelin-1 (ET-1) and endothelin-2 (ET-2) are potent stimulants of both the human umbilical artery (pEC50 7.9 and 7.5) and vein (pEC50 8.1 and 8.0). Endothelin-3 (ET-3) is inactive on the artery but contracts the vein (pEC50 7.6). |
| GO:0043410 positive regulation of MAPK cascade | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | ACCEPT | Summary: Core intracellular signaling cascade activated downstream of endothelin-3 receptor engagement. Reason: ET-3 activates the MAPK cascade downstream of endothelin receptors in human GnRH-secreting neurons and melanocytes (PMID:10770212, PMID:1917960). Supporting Evidence: PMID:10770212 Experiments with radiolabeled ET-1 and ET-3 strongly indicated the presence of two classes of binding sites, corresponding to the ETA (16,500 sites/cell) and the ETB receptors (8,700 sites/cell). Functional studies, using selective analogs, indicated that these two classes of receptors subserve distinct functions in human GnRH-secreting cells. The ETA receptor subtype mediated an increase in intracellular calcium and GnRH secretion. Conversely, stimulation of the ETB subtype induced DNA synthesis and mitogen-activated protein kinase p44ERK1 expression. |
| GO:0045597 positive regulation of cell differentiation | IGI PMID:22897442 Apolipoprotein B is a new target of the GDNF/RET and ET-3/ED... | KEEP AS NON CORE | Summary: Developmental role of endothelin-3/EDNRB signaling interacting with GDNF/RET in enteric neural crest progenitor differentiation. Reason: ET-3/EDNRB signaling coordinates with GDNF/RET to regulate the balance between proliferation and differentiation of enteric neural crest-derived progenitors (PMID:22897442); retained as a non-core developmental context downstream of EDNRB activation. Supporting Evidence: PMID:22897442 GDNF/RET and Endothelin-3 (ET-3)/EDNRB regulate survival, differentiation, migration, and proliferation of neural crest-derived cells. |
| GO:0045840 positive regulation of mitotic nuclear division | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | MODIFY | Summary: Over-specific mitotic nuclear division annotation from a thymidine-incorporation cell proliferation assay. Reason: PMID:10770212 measured [3H]thymidine incorporation (DNA synthesis and cell population proliferation) in FNC-B4 cells rather than mitotic nuclear division specifically; GO:0008284 (positive regulation of cell population proliferation) accurately captures this finding. Proposed replacements: positive regulation of cell population proliferation |
| GO:0045987 positive regulation of smooth muscle contraction | IBA GO_REF:0000033 | ACCEPT | Summary: Core downstream physiological process of endothelin-3 receptor signaling in smooth muscle. Reason: ET-3 positively regulates smooth muscle contraction in EDNRB-expressing vascular and visceral smooth muscle beds (PMID:8982507, PMID:2649896). Supporting Evidence: PMID:8982507 Endothelin-1 (ET-1) and endothelin-2 (ET-2) are potent stimulants of both the human umbilical artery (pEC50 7.9 and 7.5) and vein (pEC50 8.1 and 8.0). Endothelin-3 (ET-3) is inactive on the artery but contracts the vein (pEC50 7.6). |
| GO:0046887 positive regulation of hormone secretion | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | KEEP AS NON CORE | Summary: Downstream neuroendocrine effect of endothelin-3 stimulating gonadotropin-releasing hormone (GnRH) secretion from human olfactory neuroblasts. Reason: Maggi et al. (PMID:10770212) showed that endothelins stimulate GnRH secretion from human FNC-B4 GnRH-secreting neurons via ETA receptors; retained as a non-core neuroendocrine response downstream of endothelin receptor signaling. Supporting Evidence: PMID:10770212 The ETA receptor subtype mediated an increase in intracellular calcium and GnRH secretion. Conversely, stimulation of the ETB subtype induced DNA synthesis and mitogen-activated protein kinase p44ERK1 expression. |
| GO:0048675 axon extension | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Non-core developmental role of endothelin-3/EDNRB signaling in promoting sympathetic and enteric axon extension. Reason: Transferred by Ensembl Compara orthology from mouse Edn3, reflecting vascular and gut-wall ET-3 acting as a paracrine cue for axon extension along developing blood vessels and gut mesenchyme; retained as a non-core developmental outcome of EDNRB signaling. |
| GO:0086100 endothelin receptor signaling pathway | IDA PMID:1713452 Cloning and functional expression of human cDNA for the ETB ... | NEW | Summary: Mature endothelin-3 directly initiates the endothelin receptor signaling pathway by binding and activating EDNRB and EDNRA. Reason: Mature ET-3 is a canonical endogenous agonist of EDNRB (equipotent with ET-1) and a lower-affinity agonist of EDNRA, directly initiating endothelin receptor G-protein signaling (PMID:1713452, PMID:1917960, PMID:10770212). Supporting Evidence: PMID:1713452 COS cells transiently transfected with the cloned cDNA expressed specific, high-affinity binding sites for endothelin isopeptides and responded to the peptides with a transient increase of [Ca2+]i; endothelin-1 and endothelin-3 exhibited approximately equal potencies both in displacing 125I-labeled endothelin-1 binding and in eliciting [Ca2+]i transients. |
| GO:0160135 phospholipase C-activating endothelin receptor signaling pathway | IDA PMID:1917960 Effects of endothelins on signal transduction and proliferat... | NEW | Summary: Mature endothelin-3 activates Gq/11-coupled phospholipase C signaling, IP3 generation, and intracellular Ca2+ mobilization through EDNRB and EDNRA. Reason: ET-3 binding to human endothelin receptors stimulates inositol phosphate turnover via phospholipase C and mobilizes Ca2+ from intracellular stores (PMID:1917960, PMID:1713452). Supporting Evidence: PMID:1917960 Upon incubation with cultured cells, the mass contents of inositol 1,4,5-trisphosphate and intracellular calcium level were substantially increased by 10 nM ET-1, ET-2, and ET-3, but not by big-ET with maximal response at 80-130-s postincubation. |
| GO:0031707 endothelin A receptor binding | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | NEW | Summary: Mature endothelin-3 binds and activates the endothelin A receptor (EDNRA) at nanomolar concentrations. Reason: Although ET-3 has ~10- to 100-fold lower affinity for EDNRA than ET-1, radioligand competition and BQ-123-sensitive functional responses in human GnRH neurons and melanocytes demonstrate direct EDNRA engagement by ET-3 (PMID:10770212, PMID:1917960). Supporting Evidence: PMID:10770212 Experiments with radiolabeled ET-1 and ET-3 strongly indicated the presence of two classes of binding sites, corresponding to the ETA (16,500 sites/cell) and the ETB receptors (8,700 sites/cell). Functional studies, using selective analogs, indicated that these two classes of receptors subserve distinct functions in human GnRH-secreting cells. The ETA receptor subtype mediated an increase in intracellular calcium and GnRH secretion. Conversely, stimulation of the ETB subtype induced DNA synthesis and mitogen-activated protein kinase p44ERK1 expression. |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IDA PMID:1713452 Cloning and functional expression of human cDNA for the ETB ... | NEW | Summary: Mature endothelin-3 directly stimulates acute elevation of cytosolic Ca2+ concentration via EDNRB and in human melanocytes. Reason: ET-3 binding to human EDNRB directly elicits transient cytosolic Ca2+ elevation (PMID:1713452), and 10 nM ET-3 stimulates inositol 1,4,5-trisphosphate generation and intracellular Ca2+ elevation in human melanocytes (PMID:1917960); in human GnRH-secreting neuroblasts (PMID:10770212), ET-3 displaces radioligand at both ETA and ETB binding sites while selective-analog assays show that the ETA receptor subtype mediates intracellular calcium elevation. Supporting Evidence: PMID:1713452 COS cells transiently transfected with the cloned cDNA expressed specific, high-affinity binding sites for endothelin isopeptides and responded to the peptides with a transient increase of [Ca2+]i; endothelin-1 and endothelin-3 exhibited approximately equal potencies both in displacing 125I-labeled endothelin-1 binding and in eliciting [Ca2+]i transients. PMID:10770212 The ETA receptor subtype mediated an increase in intracellular calcium and GnRH secretion. |
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Download this section (compressed HTML)Q: To what extent does Kell metalloendopeptidase (KEL) vs. ECE-1/ECE-2 generate bioactive ET-3 in the developing human enteric nervous system in vivo?
Suggested experts: Masashi Yanagisawa, Nadege Bondurand, Anthony P. Davenport
Experiment: Determine the cryo-EM structure of human EDNRB bound to mature ET-3 in complex with Gq and Gi heterotrimers and compare residue-level contacts with the ET-1-EDNRB complex.
Hypothesis: Biased signaling of ET-3 vs. ET-1 at human EDNRB arises from distinct N-terminal loop conformations within the orthosteric pocket.
Type: Cryo-electron microscopy and BRET G-protein transducer profiling
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