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Gene Review

EDNRA  -  endothelin receptor type A

Homo sapiens

Synonyms: ET-A, ETA, ETA-R, ETAR, ETRA, ...
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Disease relevance of EDNRA


Psychiatry related information on EDNRA


High impact information on EDNRA


Chemical compound and disease context of EDNRA


Biological context of EDNRA


Anatomical context of EDNRA


Associations of EDNRA with chemical compounds

  • The ETA/ETB receptor antagonist bosentan caused a parallel shift of the concentration-contraction curve to the right at all concentrations of endothelin [16].
  • Replacement of His-150, the residue in hETB that is analogous in sequence to Tyr-129 of hETA, by either tyrosine or alanine does not affect the affinity of peptide ligands [20].
  • The endothelin (ET) family of peptides acts via two subtypes of guanine nucleotide-binding regulatory protein (G protein)-coupled receptors termed ETA and ETB [21].
  • In one study, six subjects received placebo, the ETA receptor antagonist BQ-123 alone, and BQ-123 in combination with the ETB receptor antagonist BQ-788 after pretreatment with the ACE inhibitor enalapril (E) or placebo [22].
  • Endothelin A receptor antagonism and angiotensin-converting enzyme inhibition are synergistic via an endothelin B receptor-mediated and nitric oxide-dependent mechanism [22].

Physical interactions of EDNRA

  • Furthermore, the ETA-selective antagonist BQ123 competed for the binding of these ETB-selective radioligands to this chimeric receptor, with Ki values similar to those determined by using wild-type ETA receptor and 125I-ET-1 [23].
  • 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 [24].
  • In contrast, the ETAR bound to caveolin-1 regardless of ligand binding [25].

Enzymatic interactions of EDNRA


Regulatory relationships of EDNRA

  • 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 [21].
  • Most of the potentiating effects (88%) were blocked by the ETA receptor antagonist LU135252 and slightly further blocked by the ETA/B receptor antagonist bosentan (P<0.05) [27].
  • The effect of the selective ETA receptor antagonist FR 139317 indicates that the contraction induced by ET-1 and ET-2 in both arteries and veins is mediated by ETA receptors [28].
  • We conclude that both the ETA-R and ETB-R can be regulated indistinguishably by GRK-initiated desensitization [29].
  • Abnormal expression of NFkappaB, TNFalpha, iNOS and enhanced VF are linked with the activated ET pathway and a significant reversion could be achieved by the selective endothelin A receptor antagonist darusentan [30].

Other interactions of EDNRA

  • Therefore, ET-1/ETA/ETB autocrine/paracrine loops on DCs appear to be essential for the normal maturation and function of human DCs, presenting a unique target for immunomodulatory therapies [17].
  • The family of endothelins (ET) consists of four closely related peptides, ET-1, ET-2, ET-3 and ET-4, which cause vasoconstriction, cell proliferation and myocardial effects through activation of ETA receptors [19].
  • These results suggest that endothelin-3 might have a direct role in endothelial cell proliferation as a response to injury which is not mediated by either of the currently defined ETA and ETB receptors [31].
  • The variants were: for EDNRA, a G-->A in the 5'-UTR and C-->T in exon 8; for WNK4, a tetranucleotide repeat in intron 10; and for FKBP1B, a T-->C in exon 4 [2].
  • Finally, we demonstrate that ETAR-mediated activation of PGE2-dependent signaling participates in the regulation of the invasive behavior of ovarian carcinoma cells by activating tumor-associated matrix metalloproteinase [4].

Analytical, diagnostic and therapeutic context of EDNRA


  1. 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]
  2. Association of EDNRA, but not WNK4 or FKBP1B, polymorphisms with essential hypertension. Benjafield, A.V., Katyk, K., Morris, B.J. Clin. Genet. (2003) [Pubmed]
  3. Fifteen polymorphisms in endothelin-1, endothelin-2 and endothelin-receptor-A genotyped by four duplex assays and seven simple assays on a LightCycler using hybridization probes. Arjomand-Nahad, F., Landt, O., Stangl, K., Diefenbach, K., Roots, I. Clin. Chem. Lab. Med. (2006) [Pubmed]
  4. Endothelin-1-induced prostaglandin E2-EP2, EP4 signaling regulates vascular endothelial growth factor production and ovarian carcinoma cell invasion. Spinella, F., Rosanò, L., Di Castro, V., Natali, P.G., Bagnato, A. J. Biol. Chem. (2004) [Pubmed]
  5. Enhanced expression of endothelin B receptor at protein and gene levels in human cirrhotic liver. Yokomori, H., Oda, M., Yasogawa, Y., Nishi, Y., Ogi, M., Takahashi, M., Ishii, H. Am. J. Pathol. (2001) [Pubmed]
  6. Pilot study of the endothelin-A receptor selective antagonist BMS-193884 for the treatment of erectile dysfunction. Kim, N.N., Dhir, V., Azadzoi, K.M., Traish, A.M., Flaherty, E., Goldstein, I. J. Androl. (2002) [Pubmed]
  7. The antisense homology box: a new motif within proteins that encodes biologically active peptides. Baranyi, L., Campbell, W., Ohshima, K., Fujimoto, S., Boros, M., Okada, H. Nat. Med. (1995) [Pubmed]
  8. Glucocorticoids regulate the expression of the human osteoblastic endothelin A receptor gene. Börcsök, I., Schairer, H.U., Sommer, U., Wakley, G.K., Schneider, U., Geiger, F., Niethard, F.U., Ziegler, R., Kasperk, C.H. J. Exp. Med. (1998) [Pubmed]
  9. Blocking both type A and B endothelin receptors in the kidney attenuates renal injury and prolongs survival in rats with remnant kidney. Benigni, A., Zola, C., Corna, D., Orisio, S., Facchinetti, D., Benati, L., Remuzzi, G. Am. J. Kidney Dis. (1996) [Pubmed]
  10. Mechanisms of osteoblastic metastases: role of endothelin-1. Mohammad, K.S., Guise, T.A. Clin. Orthop. Relat. Res. (2003) [Pubmed]
  11. 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]
  12. Endothelin in heart failure: a promising therapeutic target? Love, M.P., McMurray, J.J. Heart (1997) [Pubmed]
  13. 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]
  14. Variants of endothelin-1 and its receptors in atopic asthma. Mao, X.Q., Gao, P.S., Roberts, M.H., Enomoto, T., Kawai, M., Sasaki, S., Shaldon, S.R., Coull, P., Dake, Y., Adra, C.N., Hagihara, A., Shirakawa, T., Hopkin, J.M. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  15. Association between glaucoma and gene polymorphism of endothelin type A receptor. Ishikawa, K., Funayama, T., Ohtake, Y., Kimura, I., Ideta, H., Nakamoto, K., Yasuda, N., Fukuchi, T., Fujimaki, T., Murakami, A., Asaoka, R., Hotta, Y., Kanamoto, T., Tanihara, H., Miyaki, K., Mashima, Y. Mol. Vis. (2005) [Pubmed]
  16. 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]
  17. Function and survival of dendritic cells depend on endothelin-1 and endothelin receptor autocrine loops. Guruli, G., Pflug, B.R., Pecher, S., Makarenkova, V., Shurin, M.R., Nelson, J.B. Blood (2004) [Pubmed]
  18. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Shi-Wen, X., Chen, Y., Denton, C.P., Eastwood, M., Renzoni, E.A., Bou-Gharios, G., Pearson, J.D., Dashwood, M., du Bois, R.M., Black, C.M., Leask, A., Abraham, D.J. Mol. Biol. Cell (2004) [Pubmed]
  19. Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future? Spieker, L.E., Noll, G., Ruschitzka, F.T., Lüscher, T.F. J. Am. Coll. Cardiol. (2001) [Pubmed]
  20. Tyr-129 is important to the peptide ligand affinity and selectivity of human endothelin type A receptor. Lee, J.A., Elliott, J.D., Sutiphong, J.A., Friesen, W.J., Ohlstein, E.H., Stadel, J.M., Gleason, J.G., Peishoff, C.E. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  21. 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]
  22. Endothelin A receptor antagonism and angiotensin-converting enzyme inhibition are synergistic via an endothelin B receptor-mediated and nitric oxide-dependent mechanism. Goddard, J., Eckhart, C., Johnston, N.R., Cumming, A.D., Rankin, A.J., Webb, D.J. J. Am. Soc. Nephrol. (2004) [Pubmed]
  23. The ligand-receptor interactions of the endothelin systems are mediated by distinct "message" and "address" domains. Sakamoto, A., Yanagisawa, M., Sakurai, T., Nakao, K., Toyo-oka, T., Yano, M., Masaki, T. J. Cardiovasc. Pharmacol. (1993) [Pubmed]
  24. 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]
  25. Regulated interaction of endothelin B receptor with caveolin-1. Yamaguchi, T., Murata, Y., Fujiyoshi, Y., Doi, T. Eur. J. Biochem. (2003) [Pubmed]
  26. Endothelin-1 induces tyrosine phosphorylation in human blood monocytes. Chisholm, L.J., Agrawal, D.K., Pearson, T.J., Edwards, J.D. Mol. Cell. Biochem. (1996) [Pubmed]
  27. Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETB receptor blockade. Yang, Z., Krasnici, N., Lüscher, T.F. Circulation (1999) [Pubmed]
  28. Localization of endothelin immunoreactivity and demonstration of constrictory endothelin-A receptors in human coronary arteries and veins. Saetrum Opgaard, O., Adner, M., Gulbenkian, S., Edvinsson, L. J. Cardiovasc. Pharmacol. (1994) [Pubmed]
  29. Phosphorylation and desensitization of human endothelin A and B receptors. Evidence for G protein-coupled receptor kinase specificity. Freedman, N.J., Ament, A.S., Oppermann, M., Stoffel, R.H., Exum, S.T., Lefkowitz, R.J. J. Biol. Chem. (1997) [Pubmed]
  30. Up-regulated inflammatory factors endothelin, NFkappaB, TNFalpha and iNOS involved in exaggerated cardiac arrhythmias in l-thyroxine-induced cardiomyopathy are suppressed by darusentan in rats. Xia, H.J., Dai, D.Z., Dai, Y. Life Sci. (2006) [Pubmed]
  31. Endothelin-3 mediated proliferation in wounded human umbilical vein endothelial cells. Wren, A.D., Hiley, C.R., Fan, T.P. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  32. Effects of systemic endothelin A receptor antagonism in various vascular beds in men: in vivo interactions of the major blood pressure-regulating systems and associations with the GNB3 C825T polymorphism. Mitchell, A., Lückebergfeld, B., Bührmann, S., Rushentsova, U., Nürnberger, J., Siffert, W., Schäfers, R.F., Philipp, T., Wenzel, R.R. Clin. Pharmacol. Ther. (2004) [Pubmed]
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