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Gene Review

EDNRB  -  endothelin receptor type B

Homo sapiens

Synonyms: ABCDS, ET-B, ET-BR, ETB, ETBR, ...
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Disease relevance of EDNRB


Psychiatry related information on EDNRB


High impact information on EDNRB


Chemical compound and disease context of EDNRB


Biological context of EDNRB

  • We reported previously that the avian EDNRB gene is expressed in the neural fold before crest cell migration and later on in all the neural crest derivatives except, at any developmental stage, in the melanocytic lineage [14].
  • In addition, a missense mutation in the endothelin-B receptor (EDNRB) gene on chromosome 13q22 was found in an inbred Mennonite kindred affected by HSCR and associated abnormalities, demonstrating the involvement of EDNRB in HSCR pathogenesis [15].
  • We have identified two novel EDNRB mutations: a missense mutation in a sporadic case, S305N, which leads to a change of a serine to an asparagine, disrupting a putative phosphorylation site; and a single nucleotide deletion in a familial case, N378I, resulting in a truncated protein [15].
  • These data might suggest that EDNRB mutations could be dosage sensitive: heterozygosity would predispose to isolated HSCR with incomplete penetrance, while homozygosity would result in more complex neurocristopathies associating HSCR and WS features [1].
  • It is unlikely that the EDNRB variant contributes to the phenotype [16].

Anatomical context of EDNRB

  • Its expression pattern differs from that of the "classical" avian EDNRB because it is strongly expressed in melanoblasts and melanocytes [14].
  • HSCR has a complex pattern of inheritance and is sometimes associated with mutations in genes of the receptor tyrosine kinase (RET) and endothelin receptor B (EDNRB) signaling pathways, which are crucial for development of the enteric nervous system [17].
  • During the subsequent development and commitment of the melanoblast, concomitant expression of the receptors for fibroblasts growth factor (FGFR2), endothelin-B (EDNRB), and steel factor (cKIT) also appears essential for the continued survival of migrating melanoblasts [18].
  • In the EDNRB locus, two mutations were observed; a nonsense mutation of Trp to stop at codon 275, and a T insertion at nucleotide 878, in patients with aganglionosis confined to the rectosigmoid colon, and the descending colon, respectively [19].
  • The expression of EDNRB became detectable in HeLa cells after treatment with a demethylating reagent, 5'-aza-2'-deoxycytidine, which was further enhanced in the transformed cells over-expressing SOX10 [20].

Associations of EDNRB with chemical compounds


Physical interactions of EDNRB

  • Taken together, these data support the hypothesis that Asp126 and Asp133 flanking Tyr129 in TM2 of the ETA receptor play a role in defining ETA subtype-selective ligand binding but Asp147 and Asp154 that flank the His150 in TM2 of the ETB receptor do not [24].
  • We conclude that ET-1 binding to ETB receptors causes a potent growth inhibition of human myofibroblastic Ito cells, which suggests that this peptide could play a key role in the negative control of liver fibrogenesis [25].
  • The 5' region for the endothelin receptor B (EDNRB) gene is a complex CpG island giving rise to four individual transcripts initiating within the island [26].
  • In conclusion, using two cell systems, we demonstrated that the ETB receptor is functionally coupled to NOS and coordinates the generation of NO via a tyrosine kinase-dependent and a calcium/calmodulin-dependent pathway [27].

Regulatory relationships of EDNRB

  • We also demonstrated that each receptor subtype expressed on the same cell could work independently, i.e. for hETA to activate G alpha s and for hETB to activate G alpha i, resulting in dose-dependent dual effects of ET-1 on cAMP formation [28].
  • Here, we provide evidence that SOX10 regulates the expression of EDNRB gene in human melanocyte-lineage cells, as judged by RNA interference and chromatin immunoprecipitation analyses [20].
  • Conversely, stimulation of the ETB subtype induced DNA synthesis and mitogen-activated protein kinase p44ERK1 expression [29].
  • Previous research has shown that FNC-B4 cells produce and respond to ET-1 by regulating the secretion of GnRH through endothelin type A receptors and by stimulating their proliferation through endothelin type B (ETB) receptors [30].
  • The present results suggest that differences in ET-A and ET-B polymorphisms may influence the response of the vascular wall to exercise whereas ECE-1 polymorphisms may affect basal blood pressure [31].

Other interactions of EDNRB

  • Results showed that the ET-1, ETA and ETB mRNA can be detected by RT-PCR in all adrenal cortices as well as in the APA [32].
  • WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations [33].
  • Mutations in EDNRB, EDN3, and GDNF were found in four, two, and none of the patients, respectively [17].
  • In contrast, E189X and Q377X proteins, each of which lacks its C-terminal portion, activated the EDNRB promoter, whereas no activation was detected with the SOX10 proteins mutated at the DNA-binding domain, 482ins6 and S135T [34].
  • Here, we investigated the functions of SOX10 mutant proteins using the target promoters, EDNRB and MITF [34].

Analytical, diagnostic and therapeutic context of EDNRB


  1. Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. Amiel, J., Attié, T., Jan, D., Pelet, A., Edery, P., Bidaud, C., Lacombe, D., Tam, P., Simeoni, J., Flori, E., Nihoul-Fékété, C., Munnich, A., Lyonnet, S. Hum. Mol. Genet. (1996) [Pubmed]
  2. Methylation of the 5' CpG island of the endothelin B receptor gene is common in human prostate cancer. Nelson, J.B., Lee, W.H., Nguyen, S.H., Jarrard, D.F., Brooks, J.D., Magnuson, S.R., Opgenorth, T.J., Nelson, W.G., Bova, G.S. Cancer Res. (1997) [Pubmed]
  3. Downregulation of endothelin B receptor in human melanoma cell lines parallel to differentiation genes. Eberle, J., Weitmann, S., Thieck, O., Pech, H., Paul, M., Orfanos, C.E. J. Invest. Dermatol. (1999) [Pubmed]
  4. Significance of novel endothelin-B receptor gene polymorphisms in Hirschsprung's disease: predominance of a novel variant (561C/T) in patients with co-existing Down's syndrome. Zaahl, M.G., du Plessis, L., Warnich, L., Kotze, M.J., Moore, S.W. Mol. Cell. Probes (2003) [Pubmed]
  5. Endothelin B receptor gene hypermethylation in prostate adenocarcinoma. Jerónimo, C., Henrique, R., Campos, P.F., Oliveira, J., Caballero, O.L., Lopes, C., Sidransky, D. J. Clin. Pathol. (2003) [Pubmed]
  6. 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]
  7. A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease. Puffenberger, E.G., Hosoda, K., Washington, S.S., Nakao, K., deWit, D., Yanagisawa, M., Chakravart, A. Cell (1994) [Pubmed]
  8. Endothelin-1 is synthesized and inhibits cyclic adenosine monophosphate- dependent anion secretion by an autocrine/paracrine mechanism in gallbladder epithelial cells. Fouassier, L., Chinet, T., Robert, B., Carayon, A., Balladur, P., Mergey, M., Paul, A., Poupon, R., Capeau, J., Barbu, V., Housset, C. J. Clin. Invest. (1998) [Pubmed]
  9. Growth inhibitory properties of endothelin-1 in activated human hepatic stellate cells: a cyclic adenosine monophosphate-mediated pathway. Inhibition of both extracellular signal-regulated kinase and c-Jun kinase and upregulation of endothelin B receptors. Mallat, A., Préaux, A.M., Serradeil-Le Gal, C., Raufaste, D., Gallois, C., Brenner, D.A., Bradham, C., Maclouf, J., Iourgenko, V., Fouassier, L., Dhumeaux, D., Mavier, P., Lotersztajn, S. J. Clin. Invest. (1996) [Pubmed]
  10. Endothelin-1 and its receptors A and B in human aldosterone-producing adenomas. Rossi, G., Belloni, A.S., Albertin, G., Zanin, L., Biasolo, M.A., Nussdorfer, G.G., Palù, G., Pessina, A.C. Hypertension (1995) [Pubmed]
  11. Endothelin receptor antagonists in a beagle model of pulmonary hypertension: contribution to possible potential therapy? Okada, M., Yamashita, C., Okada, M., Okada, K. J. Am. Coll. Cardiol. (1995) [Pubmed]
  12. Endothelin receptor antagonists. Motte, S., McEntee, K., Naeije, R. Pharmacol. Ther. (2006) [Pubmed]
  13. Endothelin A receptor blockade does not alter PSA secretion in prostate cancer cell lines. Pecher, S., Pflug, B.R., Brink, A.K., Nelson, J.B. Prostate (2004) [Pubmed]
  14. 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]
  15. Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population. Auricchio, A., Casari, G., Staiano, A., Ballabio, A. Hum. Mol. Genet. (1996) [Pubmed]
  16. A consanguineous family with Hirschsprung disease, microcephaly, and mental retardation (Goldberg-Shprintzen syndrome). Brooks, A.S., Breuning, M.H., Osinga, J., vd Smagt, J.J., Catsman, C.E., Buys, C.H., Meijers, C., Hofstra, R.M. J. Med. Genet. (1999) [Pubmed]
  17. 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]
  18. Molecular basis of congenital hypopigmentary disorders in humans: a review. Boissy, R.E., Nordlund, J.J. Pigment Cell Res. (1997) [Pubmed]
  19. Mutation analysis of the RET, the endothelin-B receptor, and the endothelin-3 genes in sporadic cases of Hirschsprung's disease. Kusafuka, T., Wang, Y., Puri, P. J. Pediatr. Surg. (1997) [Pubmed]
  20. SOX10, in combination with Sp1, regulates the endothelin receptor type B gene in human melanocyte lineage cells. Yokoyama, S., Takeda, K., Shibahara, S. FEBS J. (2006) [Pubmed]
  21. A De Novo novel mutation of the EDNRB gene in a Taiwanese boy with Hirschsprung disease. Chen, W.C., Chang, S.S., Sy, E.D., Tsai, M.C. J. Formos. Med. Assoc. (2006) [Pubmed]
  22. Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Seo, B., Oemar, B.S., Siebenmann, R., von Segesser, L., Lüscher, T.F. Circulation (1994) [Pubmed]
  23. 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]
  24. Aspartate mutation distinguishes ETA but not ETB receptor subtype-selective ligand binding while abolishing phospholipase C activation in both receptors. Rose, P.M., Krystek, S.R., Patel, P.S., Liu, E.C., Lynch, J.S., Lach, D.A., Fisher, S.M., Webb, M.L. FEBS Lett. (1995) [Pubmed]
  25. Growth inhibitory properties of endothelin-1 in human hepatic myofibroblastic Ito cells. An endothelin B receptor-mediated pathway. Mallat, A., Fouassier, L., Préaux, A.M., Gal, C.S., Raufaste, D., Rosenbaum, J., Dhumeaux, D., Jouneaux, C., Mavier, P., Lotersztajn, S. J. Clin. Invest. (1995) [Pubmed]
  26. The endothelin receptor B (EDNRB) promoter displays heterogeneous, site specific methylation patterns in normal and tumor cells. Pao, M.M., Tsutsumi, M., Liang, G., Uzvolgyi, E., Gonzales, F.A., Jones, P.A. Hum. Mol. Genet. (2001) [Pubmed]
  27. Molecular and functional characterization of the non-isopeptide-selective ETB receptor in endothelial cells. Receptor coupling to nitric oxide synthase. Tsukahara, H., Ende, H., Magazine, H.I., Bahou, W.F., Goligorsky, M.S. J. Biol. Chem. (1994) [Pubmed]
  28. Structural basis of G protein specificity of human endothelin receptors. A study with endothelinA/B chimeras. Takagi, Y., Ninomiya, H., Sakamoto, A., Miwa, S., Masaki, T. J. Biol. Chem. (1995) [Pubmed]
  29. Expression and biological effects of endothelin-1 in human gonadotropin-releasing hormone-secreting neurons. Maggi, M., Barni, T., Fantoni, G., Mancina, R., Pupilli, C., Luconi, M., Crescioli, C., Serio, M., Vannelli, G.B. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  30. Role of endothelin-1 in the migration of human olfactory gonadotropin-releasing hormone-secreting neuroblasts. Romanelli, R.G., Barni, T., Maggi, M., Luconi, M., Failli, P., Pezzatini, A., Morelli, A., Maggi, R., Zaninetti, R., Salerno, R., Ambrosini, S., Marini, M., Rotella, C.M., Vannelli, G.B. Endocrinology (2005) [Pubmed]
  31. Polymorphism in endothelin-related genes limits exercise-induced decreases in arterial stiffness in older subjects. Iemitsu, M., Maeda, S., Otsuki, T., Sugawara, J., Tanabe, T., Jesmin, S., Kuno, S., Ajisaka, R., Miyauchi, T., Matsuda, M. Hypertension (2006) [Pubmed]
  32. Gene expression, localization, and characterization of endothelin A and B receptors in the human adrenal cortex. Rossi, G., Albertin, G., Belloni, A., Zanin, L., Biasolo, M.A., Prayer-Galetti, T., Bader, M., Nussdorfer, G.G., Palù, G., Pessina, A.C. J. Clin. Invest. (1994) [Pubmed]
  33. 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]
  34. Functional Difference of the SOX10 Mutant Proteins Responsible for the Phenotypic Variability in Auditory-Pigmentary Disorders. Yokoyama, S., Takeda, K., Shibahara, S. J. Biochem. (2006) [Pubmed]
  35. Novel endothelin B receptor transcripts with the potential of generating a new receptor. Tsutsumi, M., Liang, G., Jones, P.A. Gene (1999) [Pubmed]
  36. Clinical relationship between EDN-3 gene, EDNRB gene and Hirschsprung's disease. Duan, X.L., Zhang, X.S., Li, G.W. World J. Gastroenterol. (2003) [Pubmed]
  37. 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]
  38. Endothelin receptor expression in human lungs of newborns with congenital diaphragmatic hernia. de Lagausie, P., de Buys-Roessingh, A., Ferkdadji, L., Saada, J., Aisenfisz, S., Martinez-Vinson, C., Fund, X., Cayuela, J.M., Peuchmaur, M., Mercier, J.C., Berrebi, D. J. Pathol. (2005) [Pubmed]
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