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Gene Review

Ednra  -  endothelin receptor type A

Mus musculus

Synonyms: ET-A, ET-AR, ETa, Endothelin A receptor, Endothelin-1 receptor, ...
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Disease relevance of Ednra

  • We found that the majority of Foxc2/ETA double-mutant embryos died around 11.5 dpc and that all surviving mice had persistent truncus arteriosus [1].
  • 6. These results suggest that in experimental type 1 diabetes, blocking ETA receptors ameliorates myocardial, coronary and renal function and improves tissue oxidant status, whereas raising myocardial NO levels has neither beneficial nor deleterious effects on diabetic cardiomyopathy in this transgenic model [2].
  • It is concluded that the balance between ETA and ETB signaling is critical for maintaining tubular structure and function in the cystic kidney [3].
  • Virus-associated modulation of ETA and ETB receptor density and function was reversible with recovery from infection [4].
  • 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].

High impact information on Ednra


Chemical compound and disease context of Ednra

  • The endothelin type A (ETA) receptor antagonist BQ-123 (10 nmol;; 90 min before testing) abolishes both the early (week 1) and the late (week 5) thermal hyperalgesia [10].

Biological context of Ednra

  • We find that while Ednra gene inactivation within the mandibular arch of these Ednra conditional knockout embryos is detectable by embryonic day (E) 10.5, mandibular arch-specific gene expression is normal, as is overall mandible development [11].
  • These results suggest that while Ednra receptor signaling is crucial for early NCC patterning, subsequent Ednra signaling is not essential for mandible bone development [11].
  • To address this question, mice containing loxP recombination sequences flanking a portion of the Ednra gene were bred with transgenic mice that express Cre recombinase under control of a Dlx5/6 enhancer element [11].
  • The insulin and the endothelin type A (ETA) receptor both can couple into the heterotrimeric G protein alpha(q/11) (Galpha(q/11)), leading to Galpha(q/11) tyrosine phosphorylation, phosphatidylinositol 3-kinase activation, and subsequent stimulation of glucose transport [12].
  • In 18.5 days post coitus fetuses, ETA mRNA was most strongly expressed in osteogenic cells along craniofacial bones, but ETB mRNA was most strongly expressed in trunks of trigeminal nerve [13].

Anatomical context of Ednra

  • Collectively, our results indicate that Edn1 from the pharyngeal ectoderm signals through Ednra proteins to direct early dorsoventral patterning of the skeletogenic neural crest [14].
  • Signaling from the endothelin-A (Ednra) receptor is responsible for initiating multiple signaling pathways within neural crest cells (NCCs) [11].
  • In the lower jaw of ET-1+/- heterozygous mice, the ETA, ON, and OP mRNA positive cells were scattered in the inner and outer regions of the thick bone matrix, but in ET-1-/- homozygous mice, cells containing those mRNAs were located close to each other at the surface of thin bone matrix [13].
  • ETA-deficient mice show defects in the great arteries, primarily type B interruption of the aortic arch [1].
  • However, the function of prejunctional ETA and ETB receptor-effector systems linked to augmentation of cholinergic nerve-mediated airway smooth muscle contraction remained unaffected during respiratory tract viral infection in mice [15].

Associations of Ednra with chemical compounds

  • BQ-788 (ETB receptor antagonist) augmented the load-induced contractile response by 35% (P < 0.05), whereas bosentan (ETA/B receptor antagonist) and BQ-123 (ETA receptor antagonist) attenuated it by 34% and 56%, respectively (P < 0.05) [16].
  • Cardioprotective effects of atrasentan, an endothelin-A receptor antagonist, but not of nitric oxide in diabetic mice with myocyte-specific overexpression of endothelial nitric oxide synthase [2].
  • 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 [17].
  • Knockout of only one allele of the ETA or ETB gene appears to be sufficient for reduction of the ET-1 or IRL-1620 vasoconstrictor effects in the mesenteric and renal vascular beds of the mouse [18].
  • In BMMC, the histamine and serotonin release induced by ET-1 (10(-6) M) was inhibited by an ETA-R-specific antagonist (cyclic [D-Asp-Pro-D-Val-Leu-D-Trp]) in a dose-dependent manner, with complete inhibition at an antagonist concentration of 10(-8) M [19].

Physical interactions of Ednra

  • The data from competitive binding experiments with [125I]ET-1 and unlabeled ET-1, ET-3 and receptor subtype selective ligands yielded a single class of high affinity binding sites with ETA receptor subtype characteristics [20].

Regulatory relationships of Ednra

  • The effects of ET-1 were blocked by a specific ETA (BQ123, pA(2) 7.4) but not by a specific ETB receptor antagonist (BQ788) [21].
  • Moreover, ET-1 has a dual role in the regulation of cardiac contractility: ETA receptor-mediated increase in contractile force is suppressed by ETB receptors [16].
  • Blockade of the endothelin-A receptor was earlier shown to attenuate hypoxia-induced pulmonary hypertension and in this study, was also shown to prevent and partially reverse hypoxia-induced pulmonary vascular remodeling induced by chronic hypoxia in a newborn mouse model [22].

Other interactions of Ednra


Analytical, diagnostic and therapeutic context of Ednra

  • 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 [27].
  • The cochlear ducts of WBB6F1 (+/+) mice and mutants (W/Wv) devoid of the ICs were used for light and electron microscopic immunocytochemistry using rabbit anti-ET-1, ET-3, and ETA receptor antisera [28].
  • We also documented by using laser Doppler microprobes and imaging that administration of the ETA antagonist led to a significant increase in tumor blood flow, whereas the perfusion in control healthy tissue was not altered [29].
  • Finally, we provided evidence that acute administration of the ETA antagonist could significantly stimulate tumor oxygenation, as determined by electron paramagnetic resonance oximetry, and increase the efficacy of low-dose, clinically relevant fractionated radiotherapy [29].
  • OBJECTIVES: To examine the microcirculatory changes in the rat tibial periosteum after hindlimb ischemia and reperfusion and to evaluate the effects of endothelin-A (ET-A) receptor antagonist therapy in this condition [30].


  1. Roles of forkhead transcription factor Foxc2 (MFH-1) and endothelin receptor A in cardiovascular morphogenesis. Kanzaki-Kato, N., Tamakoshi, T., Fu, Y., Chandra, A., Itakura, T., Uezato, T., Tanaka, T., Clouthier, D.E., Sugiyama, T., Yanagisawa, M., Miura, N. Cardiovasc. Res. (2005) [Pubmed]
  2. Cardioprotective effects of atrasentan, an endothelin-A receptor antagonist, but not of nitric oxide in diabetic mice with myocyte-specific overexpression of endothelial nitric oxide synthase. Wölkart, G., Stessel, H., Saad, Z., Kirchengast, M., Brunner, F. Br. J. Pharmacol. (2006) [Pubmed]
  3. Endothelin B receptor blockade accelerates disease progression in a murine model of autosomal dominant polycystic kidney disease. Chang, M.Y., Parker, E., El Nahas, M., Haylor, J.L., Ong, A.C. J. Am. Soc. Nephrol. (2007) [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. Chronic endothelin-1 treatment leads to heterologous desensitization of insulin signaling in 3T3-L1 adipocytes. Ishibashi , K.I., Imamura, T., Sharma, P.M., Huang, J., Ugi, S., Olefsky, J.M. J. Clin. Invest. (2001) [Pubmed]
  6. Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1. Kurihara, Y., Kurihara, H., Oda, H., Maemura, K., Nagai, R., Ishikawa, T., Yazaki, Y. J. Clin. Invest. (1995) [Pubmed]
  7. IL-15 mediates immune inflammatory hypernociception by triggering a sequential release of IFN-gamma, endothelin, and prostaglandin. Verri, W.A., Cunha, T.M., Parada, C.A., Wei, X.Q., Ferreira, S.H., Liew, F.Y., Cunha, F.Q. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  8. Cardiomyocyte-specific endothelin A receptor knockout mice have normal cardiac function and an unaltered hypertrophic response to angiotensin II and isoproterenol. Kedzierski, R.M., Grayburn, P.A., Kisanuki, Y.Y., Williams, C.S., Hammer, R.E., Richardson, J.A., Schneider, M.D., Yanagisawa, M. Mol. Cell. Biol. (2003) [Pubmed]
  9. Pharmacological inactivation of the endothelin type A receptor in the early chick embryo: a model of mispatterning of the branchial arch derivatives. Kempf, H., Linares, C., Corvol, P., Gasc, J.M. Development (1998) [Pubmed]
  10. Implantation of tumoral XC cells induces chronic, endothelin-dependent, thermal hyperalgesia in mice. Baamonde, A., Lastra, A., Fresno, M.F., Llames, S., Meana, A., Hidalgo, A., Menéndez, L. Cell. Mol. Neurobiol. (2004) [Pubmed]
  11. Deletion of the endothelin-A receptor gene within the developing mandible. Ruest, L.B., Kedzierski, R., Yanagisawa, M., Clouthier, D.E. Cell Tissue Res. (2005) [Pubmed]
  12. beta -Arrestin-mediated recruitment of the Src family kinase Yes mediates endothelin-1-stimulated glucose transport. Imamura, T., Huang, J., Dalle, S., Ugi, S., Usui, I., Luttrell, L.M., Miller, W.E., Lefkowitz, R.J., Olefsky, J.M. J. Biol. Chem. (2001) [Pubmed]
  13. Gene expression of bone matrix proteins and endothelin receptors in endothelin-1-deficient mice revealed by in situ hybridization. Kitano, Y., Kurihara, H., Kurihara, Y., Maemura, K., Ryo, Y., Yazaki, Y., Harii, K. J. Bone Miner. Res. (1998) [Pubmed]
  14. Requirements for Endothelin type-A receptors and Endothelin-1 signaling in the facial ectoderm for the patterning of skeletogenic neural crest cells in zebrafish. Nair, S., Li, W., Cornell, R., Schilling, T.F. Development (2007) [Pubmed]
  15. Influence of respiratory tract viral infection on endothelin-1-induced potentiation of cholinergic nerve-mediated contraction in mouse trachea. Carr, M.J., Goldie, R.G., Henry, P.J. Br. J. Pharmacol. (1996) [Pubmed]
  16. Dual role of endothelin-1 via ETA and ETB receptors in regulation of cardiac contractile function in mice. Piuhola, J., Mäkinen, M., Szokodi, I., Ruskoaho, H. Am. J. Physiol. Heart Circ. Physiol. (2003) [Pubmed]
  17. 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]
  18. Pharmacology of endothelins in vascular circuits of normal or heterozygous endothelin-A or endothelin-B knockout transgenic mice. Berthiaume, N., Yanagisawa, M., Yanagisawa, H., deWit, D., D'Orléans-Juste, P. J. Cardiovasc. Pharmacol. (1998) [Pubmed]
  19. IL-4 renders mast cells functionally responsive to endothelin-1. Egger, D., Geuenich, S., Denzlinger, C., Schmitt, E., Mailhammer, R., Ehrenreich, H., Dörmer, P., Hültner, L. J. Immunol. (1995) [Pubmed]
  20. A transformed murine Leydig cell line expresses the ETA receptor subtype. Ergul, A., Glassberg, M.K., Freeman, M.E., Puett, D. Mol. Cell. Biochem. (1994) [Pubmed]
  21. 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]
  22. Endothelin-A receptor blockade inhibits the effects of hypoxia on the newborn lung vasculature. Ambalavanan, N. ScientificWorldJournal (2006) [Pubmed]
  23. Increased endothelin and endothelin receptor mRNA expression in polycystic kidneys of cpk mice. Nakamura, T., Ebihara, I., Fukui, M., Osada, S., Tomino, Y., Masaki, T., Goto, K., Furuichi, Y., Koide, H. J. Am. Soc. Nephrol. (1993) [Pubmed]
  24. Endothelin-1 is involved in the growth promotion of vascular smooth muscle cells by hyaluronic acid. Tanaka, Y., Makiyama, Y., Mitsui, Y. International journal of cardiology. (2000) [Pubmed]
  25. Signaling pathways crucial for craniofacial development revealed by endothelin-A receptor-deficient mice. Clouthier, D.E., Williams, S.C., Yanagisawa, H., Wieduwilt, M., Richardson, J.A., Yanagisawa, M. Dev. Biol. (2000) [Pubmed]
  26. A potential role for the endothelin ETA receptor in salt-sensitive hypertension of the proANP gene-disrupted mouse. O'Tierney, P.F., Angelis, E., Tse, M.Y., Pang, J.J., Adams, M.A., Pang, S.C. Mol. Cell. Biochem. (2005) [Pubmed]
  27. Endothelin receptors in light-induced retinal degeneration. Torbidoni, V., Iribarne, M., Suburo, A.M. Exp. Biol. Med. (Maywood) (2006) [Pubmed]
  28. The significance of endothelin for generation of endocochlear potential. Fujimura, T., Furukawa, H., Doi, Y., Fujimoto, S. J. Cardiovasc. Pharmacol. (1998) [Pubmed]
  29. Endothelin-1 is a critical mediator of myogenic tone in tumor arterioles: implications for cancer treatment. Sonveaux, P., Dessy, C., Martinive, P., Havaux, X., Jordan, B.F., Gallez, B., Grégoire, V., Balligand, J.L., Feron, O. Cancer Res. (2004) [Pubmed]
  30. Endothelin-a receptor antagonist treatment improves the periosteal microcirculation after hindlimb ischemia and reperfusion in the rat. Wolfárd, A., Császár, J., Gera, L., Petri, A., Simonka, J.A., Balogh, A., Boros, M. Microcirculation (New York, N.Y. : 1994) (2002) [Pubmed]
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