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Gene Review

Ednrb  -  endothelin receptor type B

Mus musculus

Synonyms: AU022549, ET-B, ET-BR, ETR-b, ETb, ...
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Disease relevance of Ednrb

  • This 1-kb enhancer is activated as the ENS precursors approach the colon, and partial deletion of this enhancer at the endogenous Ednrb locus results in pigmented mice that die postnatally from megacolon [1].
  • Phenotype variation in two-locus mouse models of Hirschsprung disease: tissue-specific interaction between Ret and Ednrb [2].
  • Fourth, mice that are double heterozygous for loss-of-function mutations in Sox10 and Ednrb do not demonstrate synergistically increased hypopigmentation compared to mice that are single heterozygotes for either mutation alone, suggesting a lack of direct genetic interaction between these genes [3].
  • 1. In the current study, the density and function of ETA and ETB receptors in mouse tracheal airway smooth muscle were determined over the time course of respiratory tract infection with influenza A/PR-8/34 virus [4].
  • Virus-associated modulation of ETA and ETB receptor density and function was reversible with recovery from infection [4].

Psychiatry related information on Ednrb

  • We have established two locus noncomplementation assays in mice, using allelic series at Ednrb in the context of Ret kinase-null heterozygotes, to understand the clinical presentation, incomplete penetrance, variation in length of aganglionic segment, and sex bias observed in human HSCR patients [2].
  • To determine the fate of Ednrb-expressing cells during this critical period, we generated a strain of mice with the bacterial beta-galactosidase (lacZ) gene inserted downstream of the endogenous Ednrb promoter [5].

High impact information on Ednrb

  • The expression of Ednrb is required at a defined time period during the migration of the precursors of the enteric nervous system (ENS) into the colon [1].
  • In this study, we describe a conserved spatiotemporal ENS enhancer of Ednrb [1].
  • One of the primary genes affected in HSCR encodes the G protein-coupled endothelin receptor-B (EDNRB) [1].
  • Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease [6].
  • These findings indicate an essential role for EDNRB in the development of two neural crest-derived cell lineages, myenteric ganglion neurons and epidermal melanocytes [7].

Chemical compound and disease context of Ednrb

  • The administration of the selective ETA antagonist BQ-123 (1-10 nmol) antagonized the thermal hyperalgesia detected by the unilateral hot plate test, observed in both inflammatory models, whereas the administration of the ETB selective antagonist BQ-788 (17.7 nmol) failed to modify this [8].

Biological context of Ednrb

  • To determine when EDNRB signalling is required during embryogenesis, we have exploited the tetracycline-inducible system to generate strains of mice in which the endogenous Ednrb locus is under the control of the tetracycline-dependant transactivators tTa or rtTA [9].
  • Consistent with this, neither Ednrb nor Edn3 mRNA was detected in 3/3 tested immortal lines of mouse melanoblasts and 5/5 lines of melanocytes, of various genotypes [10].
  • However, it is hard to assess cell differentiation in these mixed cultures, and it is not known whether Ednrb has any role in the postnatal melanocytic lineage [10].
  • Mutation analysis revealed that their Ednrb lacked 318 nucleotides encoding Ednrb transmembrane domains owing to deletion of exons 2 and 3 [11].
  • A genome wide scan confirmed the presence of a QTL (peak LOD = 6.4) on chromosome 14 near the piebald (Ednrb) and 5-hydroxytryptamine(2A) (Htr2a) loci [12].

Anatomical context of Ednrb

  • The results suggest that Ednrb plays a significant role during melanocyte differentiation and effects melanocyte development by both cell non-autonomous and cell-autonomous signaling mechanisms [13].
  • The endothelin receptor B gene (Ednrb) encodes a G-protein-coupled receptor that is expressed in a variety of cell types and is specifically required for the development of neural crest-derived melanocytes and enteric ganglia [13].
  • By comparing Ednrb(lacZ)/+ and Ednrb(lacZ)/Ednrb(lacZ) embryos, we determined that the Ednrb pathway is not required for the initial specification and dispersal of melanoblasts and ENS precursors from the neural crest progenitors [5].
  • 3T3-F442A adipocytes express the mRNAs for prepro-ET-1 and the ET-A receptor subtype, but not for the ET-B subtype [14].
  • Quail Ednrb is expressed in NCCs migrating along the ventral pathway, which gives rise to the peripheral nervous system, including enteric ganglia [15].

Associations of Ednrb with chemical compounds

  • The increased transcription can be attributed to ETB receptor blockade, because BQ-788, but not BQ-123, increased PPE-1 transcription [16].
  • Bosentan, a dual ETA/B receptor antagonist, and BQ788 (ETB receptor antagonist) treatment resulted in a 1.6-fold and 1.3-fold increase, respectively in luciferase activity as compared with the untreated control [16].
  • Ednrb27Pub mice harbor a mutation at a critical proline residue in the fifth transmembrane domain of the EDNRB protein [17].
  • The nonselective ETA/ETB receptor antagonist PD 142893 blocked both ET and S6c-induced enhancement of the PTH responses [18].
  • The antagonists used were BQ-123, an ETA antagonist, BQ-788, an ETB antagonist, and SB209670, an ET(A&B) antagonist [19].

Physical interactions of Ednrb

  • The development of melanocytes from neural crest-derived precursor cells depends on signaling by the receptor tyrosine kinase KIT and the G protein-coupled endothelin receptor B (EDNRB) pathways [20].

Other interactions of Ednrb


Analytical, diagnostic and therapeutic context of Ednrb

  • Titration of Ednrb in the presence of half the genetic dose of Ret determines the presentation of an enteric phenotype in these strains, revealing or abrogating a sex bias in disease expression depending on the genotype at Ednrb [2].
  • To address the question of whether melanocyte development depends entirely on a cell-autonomous action of Ednrb, we performed a series of tissue recombination experiments in vitro, using neural crest cell cultures from mouse embryos carrying a novel Ednrb-null allele characterized by the insertion of a lacZ marker gene [13].
  • Using confocal double immunofluorescence, we have observed that ET-A seems to be localized in bipolar cell dendrites, whereas ET-B is localized in horizontal cells [25].
  • Nevertheless, in this animal model of ETB receptor deficiency, endothelial function is impaired independent of salt-enriched diet or hypertension [26].
  • The expression of ETB receptor mRNAs in Bergmann glial cells was revealed by single-cell RT-PCR [27].


  1. Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest-derived enteric neuron precursors. Zhu, L., Lee, H.O., Jordan, C.S., Cantrell, V.A., Southard-Smith, E.M., Shin, M.K. Nat. Genet. (2004) [Pubmed]
  2. Phenotype variation in two-locus mouse models of Hirschsprung disease: tissue-specific interaction between Ret and Ednrb. McCallion, A.S., Stames, E., Conlon, R.A., Chakravarti, A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  3. Genetic evidence does not support direct regulation of EDNRB by SOX10 in migratory neural crest and the melanocyte lineage. Hakami, R.M., Hou, L., Baxter, L.L., Loftus, S.K., Southard-Smith, E.M., Incao, A., Cheng, J., Pavan, W.J. Mech. Dev. (2006) [Pubmed]
  4. Time course of changes in ETB receptor density and function in tracheal airway smooth muscle during respiratory tract viral infection in mice. Carr, M.J., Goldie, R.G., Henry, P.J. Br. J. Pharmacol. (1996) [Pubmed]
  5. The endothelin receptor-B is required for the migration of neural crest-derived melanocyte and enteric neuron precursors. Lee, H.O., Levorse, J.M., Shin, M.K. Dev. Biol. (2003) [Pubmed]
  6. Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease. Carrasquillo, M.M., McCallion, A.S., Puffenberger, E.G., Kashuk, C.S., Nouri, N., Chakravarti, A. Nat. Genet. (2002) [Pubmed]
  7. Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Hosoda, K., Hammer, R.E., Richardson, J.A., Baynash, A.G., Cheung, J.C., Giaid, A., Yanagisawa, M. Cell (1994) [Pubmed]
  8. Involvement of endogenous endothelins in thermal and mechanical inflammatory hyperalgesia in mice. Baamonde, A., Lastra, A., Villazón, M., Bordallo, J., Hidalgo, A., Menéndez, L. Naunyn Schmiedebergs Arch. Pharmacol. (2004) [Pubmed]
  9. The temporal requirement for endothelin receptor-B signalling during neural crest development. Shin, M.K., Levorse, J.M., Ingram, R.S., Tilghman, S.M. Nature (1999) [Pubmed]
  10. Impaired growth and differentiation of diploid but not immortal melanoblasts from endothelin receptor B mutant (piebald) mice. Sviderskaya, E.V., Easty, D.J., Bennett, D.C. Dev. Dyn. (1998) [Pubmed]
  11. A mouse model of Waardenburg syndrome type 4 with a new spontaneous mutation of the endothelin-B receptor gene. Matsushima, Y., Shinkai, Y., Kobayashi, Y., Sakamoto, M., Kunieda, T., Tachibana, M. Mamm. Genome (2002) [Pubmed]
  12. Identification of quantitative trait loci for haloperidol-induced catalepsy on mouse chromosome 14. Rasmussen, E., Cipp, L., Hitzemann, R. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  13. Cell-autonomous and cell non-autonomous signaling through endothelin receptor B during melanocyte development. Hou, L., Pavan, W.J., Shin, M.K., Arnheiter, H. Development (2004) [Pubmed]
  14. Endothelin-1 inhibits TNF alpha-induced iNOS expression in 3T3-F442A adipocytes. Mérial-Kieny, C., Lonchampt, M., Cogé, F., Verwaerde, P., Galizzi, J.P., Boutin, J.A., Lafontan, M., Levens, N., Galitzky, J., Félétou, M. Br. J. Pharmacol. (2003) [Pubmed]
  15. Ednrb2 orients cell migration towards the dorsolateral neural crest pathway and promotes melanocyte differentiation. Pla, P., Alberti, C., Solov'eva, O., Pasdar, M., Kunisada, T., Larue, L. Pigment Cell Res. (2005) [Pubmed]
  16. Endothelin B receptor antagonist increases preproendothelin-1 transcription in bovine aortic endothelial cells and in vivo. Peled, M., Shaish, A., Frishman, L., Cohen, H., Tal, R., Harats, D. J. Cardiovasc. Pharmacol. (2006) [Pubmed]
  17. Molecular characterization of four induced alleles at the Ednrb locus. Shin, M.K., Russell, L.B., Tilghman, S.M. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  18. EndothelinB receptor activation enhances parathyroid hormone-induced calcium signals in UMR-106 cells. Lee, S.K., Stern, P.H. J. Bone Miner. Res. (1995) [Pubmed]
  19. Endothelin receptor antagonists inhibit antigen-induced lung inflammation in mice. Fujitani, Y., Trifilieff, A., Tsuyuki, S., Coyle, A.J., Bertrand, C. Am. J. Respir. Crit. Care Med. (1997) [Pubmed]
  20. Cooperative and indispensable roles of endothelin 3 and KIT signalings in melanocyte development. Aoki, H., Motohashi, T., Yoshimura, N., Yamazaki, H., Yamane, T., Panthier, J.J., Kunisada, T. Dev. Dyn. (2005) [Pubmed]
  21. Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte development. Stanchina, L., Baral, V., Robert, F., Pingault, V., Lemort, N., Pachnis, V., Goossens, M., Bondurand, N. Dev. Biol. (2006) [Pubmed]
  22. ET-1-induced bronchoconstriction is mediated via ETB receptor in mice. Nagase, T., Aoki, T., Oka, T., Fukuchi, Y., Ouchi, Y. J. Appl. Physiol. (1997) [Pubmed]
  23. The first inner loop of endothelin receptor type B is necessary for specific coupling to Galpha 13. Liu, B., Wu, D. J. Biol. Chem. (2003) [Pubmed]
  24. Interleukin-1beta attenuates endothelin B receptor-mediated airway contractions in a murine in vitro model of asthma: roles of endothelin converting enzyme and mitogen-activated protein kinase pathways. Zhang, Y., Adner, M., Cardell, L.O. Clin. Exp. Allergy (2004) [Pubmed]
  25. Endothelin receptors in light-induced retinal degeneration. Torbidoni, V., Iribarne, M., Suburo, A.M. Exp. Biol. Med. (Maywood) (2006) [Pubmed]
  26. Endothelin B receptor-deficient mice develop endothelial dysfunction independently of salt loading. Quaschning, T., Rebhan, B., Wunderlich, C., Wanner, C., Richter, C.M., Pfab, T., Bauer, C., Kraemer-Guth, A., Galle, J., Yanagisawa, M., Hocher, B. J. Hypertens. (2005) [Pubmed]
  27. Bergmann glial cells in situ express endothelinB receptors linked to cytoplasmic calcium signals. Tuschick, S., Kirischuk, S., Kirchhoff, F., Liefeldt, L., Paul, M., Verkhratsky, A., Kettenmann, H. Cell Calcium (1997) [Pubmed]
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