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Gene Review

EDN3  -  endothelin 3

Homo sapiens

Synonyms: ET-3, ET3, Endothelin-3, HSCR4, PPET3, ...
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Disease relevance of EDN3

  • We postulate that defects in the human EDN3 gene may cause Hirschsprung's disease [1].
  • Novel EDNRB mutations have been detected in non-syndromic HD patients with heterozygous forms, and homozygous mutations of the EDNRB or the EDN3 genes have been reported in HD patients associated with type 2 Waardenburg syndrome [2].
  • The same held true for the corresponding ET-3 plasma concentrations in cirrhosis (19.3 +/- 1.6 pg/mL, 20.5 +/- 1.5 pg/mL, and 18.4 +/- 1.5 pg/mL, respectively) compared with controls (11.1 +/- 1.8 pg/mL, 11.3 +/- 1.5 pg/mL, and 10.1 +/- 1.7 pg/mL, respectively; P < .01) [3].
  • ET-3, an ETB-selective agonist, also had no effect on prostate cancer growth [4].
  • Moderate to strong staining was seen in 72% and 64% of carcinomas for ET-1 and ET-3, respectively [5].

Psychiatry related information on EDN3

  • In addition, the results of the RD3 and ET3 immunostains clearly explain for the first time the presence of both 3R and 4R tau isoforms in preparations of insoluble tau from some Pick's disease cases [6].

High impact information on EDN3


Chemical compound and disease context of EDN3


Biological context of EDN3


Anatomical context of EDN3


Associations of EDN3 with chemical compounds


Physical interactions of EDN3

  • Endothelin-2 and sarafotoxin S6B inhibited [125I]-PD151242 binding to renal tissue whereas ET-3 and sarafotoxin S6C were less effective [27].
  • Ligand binding studies of the cloned receptors expressed in COS cells confirmed that they were pharmacologically ETAR and ETBR subtypes; although the selective antagonist BQ123 showed a potency similar to ET-3 in displacing 125I-ET-1 binding to ETAR [28].

Regulatory relationships of EDN3

  • ET-3 also stimulated growth (36 +/- 3.8%) but was less potent than ET-1 (threshold, 10(-9) M; maximal, 10(-7) M) [29].
  • Neither ET-1 nor ET-3 induces secretion of CXCL8 in primary human melanocytes; thus, this response may be specific for melanocytic cells that have undergone malignant transformation [30].
  • We found that the vasoactive peptides endothelin (ET)-1 and ET-3 stimulated the synthesis of VEGF protein 3-4-fold in cultured human vascular smooth muscle cells, comparable in magnitude to hypoxia [31].
  • Consistent with such a role, the proportion of Sox10-expressing progenitors in the total population of enteric neural crest cells is reduced in the gut of endothelin 3-deficient embryos [32].
  • In addition, ET-3 (1 to 100 nM) stimulated ADM release only from ET(A)/ET(B) isolates, implicating the ET(B) receptor in this response [33].

Other interactions of EDN3

  • Although endothelin-3 caused significantly less forearm vasoconstriction than endothelin-1 at low doses, vasoconstriction was similar to the two isopeptides at the highest dose (60 pmol/min) [19].
  • EDN1, EDN2, and EDN3 were mapped to 6p23-p24, 1p34, and 20q13.2-q13.3, respectively [34].
  • WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations [35].
  • METHODS: Using PCR amplification and direct sequencing, we screened for mutations and polymorphisms in the coding regions and intron/exon boundaries of the RET, GDNF, EDNRB, and EDN3 genes of 84 HSCR patients and 96 ethnically matched controls [36].
  • In addition, endothelin-3 (ET-3) and N-succinyl-[Glu9, Ala11, 15]-ET-1-1620, both selective ET(B) agonists, are potent upregulators of MCAM [37].

Analytical, diagnostic and therapeutic context of EDN3

  • Reverse transcription-polymerase chain reaction (RT-PCR) was performed to evaluate the relative amount of EDN3 and EDNRB mRNA [38].
  • Arterial and venous plasma samples were obtained simultaneously, and ET-1 and ET-3 concentrations were determined in extracted plasma by two separate radioimmunoassays [3].
  • The conversion to ET-3 was confirmed with sandwich EIA by monoclonal antibodies, the elution profile of HPLC, and intracellular calcium mobilization in CHO-K1 cells expressing recombinant human ET(B) receptors [39].
  • 1. Using front-surface fluorometry of fura-2 and medial strips of the porcine coronary artery, we investigated mechanisms by which endothelin-1 (ET-1) and ET-3 function as vasoconstrictors [25].
  • Plasma immunoreactive endothelin-3 (ir-ET-3) concentrations were measured by a sandwich-enzyme immunoassay (sandwich-EIA) for endothelin-3 (ET-3) [40].


  1. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Baynash, A.G., Hosoda, K., Giaid, A., Richardson, J.A., Emoto, N., Hammer, R.E., Yanagisawa, M. Cell (1994) [Pubmed]
  2. Mutations of the endothelin-B receptor and endothelin-3 genes in Hirschsprung's disease. Kusafuka, T., Puri, P. Pediatr. Surg. Int. (1997) [Pubmed]
  3. Endothelin-1 and -3 plasma concentrations in patients with cirrhosis: role of splanchnic and renal passage and liver function. Gerbes, A.L., Møller, S., Gülberg, V., Henriksen, J.H. Hepatology (1995) [Pubmed]
  4. Endothelin-1 production and decreased endothelin B receptor expression in advanced prostate cancer. Nelson, J.B., Chan-Tack, K., Hedican, S.P., Magnuson, S.R., Opgenorth, T.J., Bova, G.S., Simons, J.W. Cancer Res. (1996) [Pubmed]
  5. Augmented expression of endothelin-1, endothelin-3 and the endothelin-B receptor in breast carcinoma. Alanen, K., Deng, D.X., Chakrabarti, S. Histopathology (2000) [Pubmed]
  6. The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy. Hogg, M., Grujic, Z.M., Baker, M., Demirci, S., Guillozet, A.L., Sweet, A.P., Herzog, L.L., Weintraub, S., Mesulam, M.M., LaPointe, N.E., Gamblin, T.C., Berry, R.W., Binder, L.I., de Silva, R., Lees, A., Espinoza, M., Davies, P., Grover, A., Sahara, N., Ishizawa, T., Dickson, D., Yen, S.H., Hutton, M., Bigio, E.H. Acta Neuropathol. (2003) [Pubmed]
  7. A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Hofstra, R.M., Osinga, J., Tan-Sindhunata, G., Wu, Y., Kamsteeg, E.J., Stulp, R.P., van Ravenswaaij-Arts, C., Majoor-Krakauer, D., Angrist, M., Chakravarti, A., Meijers, C., Buys, C.H. Nat. Genet. (1996) [Pubmed]
  8. Endothelin-3 frameshift mutation in congenital central hypoventilation syndrome. Bolk, S., Angrist, M., Xie, J., Yanagisawa, M., Silvestri, J.M., Weese-Mayer, D.E., Chakravarti, A. Nat. Genet. (1996) [Pubmed]
  9. Plasma endothelin immunoreactivity in liver disease and the hepatorenal syndrome. Moore, K., Wendon, J., Frazer, M., Karani, J., Williams, R., Badr, K. N. Engl. J. Med. (1992) [Pubmed]
  10. International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. Davenport, A.P. Pharmacol. Rev. (2002) [Pubmed]
  11. Ursodeoxycholic acid reduces increased circulating endothelin 2 in primary biliary cirrhosis. Dimoulios, P., Kolios, G., Notas, G., Matrella, E., Xidakis, C., Koulentaki, M., Tsagarakis, N., Kouroumalis, A., Kouroumalis, E. Aliment. Pharmacol. Ther. (2005) [Pubmed]
  12. Retinal blood flow in diabetes. Clermont, A.C., Bursell, S.E. Microcirculation (New York, N.Y. : 1994) (2007) [Pubmed]
  13. Influence of hypercholesterolemia and endothelin-3 pre-treatment on the effects of shear forces on platelet aggregation and cyclic GMP content. Gagnet, C., Devynck, M.A., Simon, A., Levenson, J. Atherosclerosis (1999) [Pubmed]
  14. Comparison of photodynamic targets in a carcinoma cell line and its mitochondrial DNA-deficient derivative. Morgan, J., Potter, W.R., Oseroff, A.R. Photochem. Photobiol. (2000) [Pubmed]
  15. Expression of endothelin 3 by mesenchymal cells of embryonic mouse caecum. Leibl, M.A., Ota, T., Woodward, M.N., Kenny, S.E., Lloyd, D.A., Vaillant, C.R., Edgar, D.H. Gut (1999) [Pubmed]
  16. Reduced endothelin-3 expression in sporadic Hirschsprung disease. Kenny, S.E., Hofstra, R.M., Buys, C.H., Vaillant, C.R., Lloyd, D.A., Edgar, D.H. The British journal of surgery. (2000) [Pubmed]
  17. The gene for the novel vasoactive peptide endothelin 3 (EDN3) is localized to human chromosome 20q13.2-qter. Rao, V.V., Löffler, C., Hansmann, I. Genomics (1991) [Pubmed]
  18. Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b. Weese-Mayer, D.E., Berry-Kravis, E.M., Zhou, L., Maher, B.S., Silvestri, J.M., Curran, M.E., Marazita, M.L. Am. J. Med. Genet. A (2003) [Pubmed]
  19. Endothelin ETA and ETB receptors cause vasoconstriction of human resistance and capacitance vessels in vivo. Haynes, W.G., Strachan, F.E., Webb, D.J. Circulation (1995) [Pubmed]
  20. Cloning and characterization of a novel endothelin receptor subtype in the avian class. Lecoin, L., Sakurai, T., Ngo, M.T., Abe, Y., Yanagisawa, M., Le Douarin, N.M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  21. Cloning and characterization of an endothelin-3 specific receptor (ETC receptor) from Xenopus laevis dermal melanophores. Karne, S., Jayawickreme, C.K., Lerner, M.R. J. Biol. Chem. (1993) [Pubmed]
  22. Transient expression of endothelins in the amoeboid microglial cells in the developing rat brain. Wu, C.Y., Kaur, C., Lu, J., Cao, Q., Guo, C.H., Zhou, Y., Sivakumar, V., Ling, E.A. Glia (2006) [Pubmed]
  23. Reduced endothelin converting enzyme-1 and endothelin-3 mRNA in the developing bowel of male mice may increase expressivity and penetrance of Hirschsprung disease-like distal intestinal aganglionosis. Vohra, B.P., Planer, W., Armon, J., Fu, M., Jain, S., Heuckeroth, R.O. Dev. Dyn. (2007) [Pubmed]
  24. Evidence for heterogeneity of endothelin receptor distribution in human coronary artery. Godfraind, T. Br. J. Pharmacol. (1993) [Pubmed]
  25. Endothelin-1 and endothelin-3 regulate differently vasoconstrictor responses of smooth muscle of the porcine coronary artery. Ushio-Fukai, M., Nishimura, J., Kobayashi, S., Kanaide, H. Br. J. Pharmacol. (1995) [Pubmed]
  26. Endothelin converting enzyme (ECE) activity in human vascular smooth muscle. Maguire, J.J., Johnson, C.M., Mockridge, J.W., Davenport, A.P. Br. J. Pharmacol. (1997) [Pubmed]
  27. [125I]-PD151242: a selective ligand for endothelin ETA receptors in human kidney which localizes to renal vasculature. Davenport, A.P., Kuc, R.E., Hoskins, S.L., Karet, F.E., Fitzgerald, F. Br. J. Pharmacol. (1994) [Pubmed]
  28. Molecular characterization and regulation of the human endothelin receptors. Elshourbagy, N.A., Korman, D.R., Wu, H.L., Sylvester, D.R., Lee, J.A., Nuthalaganti, P., Bergsma, D.J., Kumar, C.S., Nambi, P. J. Biol. Chem. (1993) [Pubmed]
  29. BQ123, an ETA receptor antagonist, inhibits endothelin-1-mediated proliferation of human pulmonary artery smooth muscle cells. Zamora, M.A., Dempsey, E.C., Walchak, S.J., Stelzner, T.J. Am. J. Respir. Cell Mol. Biol. (1993) [Pubmed]
  30. Endothelin-1 induces CXCL1 and CXCL8 secretion in human melanoma cells. Mangahas, C.R., dela Cruz, G.V., Friedman-Jiménez, G., Jamal, S. J. Invest. Dermatol. (2005) [Pubmed]
  31. Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion. Pedram, A., Razandi, M., Hu, R.M., Levin, E.R. J. Biol. Chem. (1997) [Pubmed]
  32. Maintenance of mammalian enteric nervous system progenitors by SOX10 and endothelin 3 signalling. Bondurand, N., Natarajan, D., Barlow, A., Thapar, N., Pachnis, V. Development (2006) [Pubmed]
  33. Differential adrenomedullin release and endothelin receptor expression in distinct subpopulations of human airway smooth-muscle cells. Upton, P.D., Wharton, J., Davie, N., Ghatei, M.A., Smith, D.M., Morrell, N.W. Am. J. Respir. Cell Mol. Biol. (2001) [Pubmed]
  34. Chromosomal assignments of the human endothelin family genes: the endothelin-1 gene (EDN1) to 6p23-p24, the endothelin-2 gene (EDN2) to 1p34, and the endothelin-3 gene (EDN3) to 20q13.2-q13.3. Arinami, T., Ishikawa, M., Inoue, A., Yanagisawa, M., Masaki, T., Yoshida, M.C., Hamaguchi, H. Am. J. Hum. Genet. (1991) [Pubmed]
  35. Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain. Touraine, R.L., Attié-Bitach, T., Manceau, E., Korsch, E., Sarda, P., Pingault, V., Encha-Razavi, F., Pelet, A., Augé, J., Nivelon-Chevallier, A., Holschneider, A.M., Munnes, M., Doerfler, W., Goossens, M., Munnich, A., Vekemans, M., Lyonnet, S. Am. J. Hum. Genet. (2000) [Pubmed]
  36. Highly recurrent RET mutations and novel mutations in genes of the receptor tyrosine kinase and endothelin receptor B pathways in Chinese patients with sporadic Hirschsprung disease. Garcia-Barceló, M., Sham, M.H., Lee, W.S., Lui, V.C., Chen, B.L., Wong, K.K., Wong, J.S., Tam, P.K. Clin. Chem. (2004) [Pubmed]
  37. Endothelin-1 upregulates MCAM in melanocytes. Mangahas, C.R., dela Cruz, G.V., Schneider, R.J., Jamal, S. J. Invest. Dermatol. (2004) [Pubmed]
  38. Altered endothelin-3 and endothelin-B receptor mRNA expression in Hirschsprung's disease. Oue, T., Puri, P. J. Pediatr. Surg. (1999) [Pubmed]
  39. Purification of a novel endothelin-converting enzyme specific for big endothelin-3. Hasegawa, H., Hiki, K., Sawamura, T., Aoyama, T., Okamoto, Y., Miwa, S., Shimohama, S., Kimura, J., Masaki, T. FEBS Lett. (1998) [Pubmed]
  40. Endothelin-3 concentrations in human plasma: the increased concentrations in patients undergoing haemodialysis. Suzuki, N., Matsumoto, H., Miyauchi, T., Goto, K., Masaki, T., Tsuda, M., Fujino, M. Biochem. Biophys. Res. Commun. (1990) [Pubmed]
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