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Endothelin receptors C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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More detailed introduction 
Endothelin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Endothelin Receptors [5]) are activated by the endogenous 21 amino-acid peptides endothelins 1-3 (endothelin-1 (EDN1, P05305), endothelin-2 (EDN2, P20800) and endothelin-3 (EDN3, P14138)).
Receptors
Targets of relevance to immunopharmacology are highlighted in blue
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ETA receptor C
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ETB receptor C
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Further reading
* Key recommended reading is highlighted with an asterisk
Abraham GR, Kuc RE, Althage M, Greasley PJ, Ambery P, Maguire JJ, Wilkinson IB, Hoole SP, Cheriyan J, Davenport AP. (2022) Endothelin-1 is increased in the plasma of patients hospitalised with Covid-19. J Mol Cell Cardiol, [Epub ahead of print]. DOI: 10.1016/j.yjmcc.2022.03.007 [PMID:35339512]
Bagnato A, Rosanò L. (2008) The endothelin axis in cancer. Int J Biochem Cell Biol, 40 (8): 1443-51. [PMID:18325824]
Barr TP, Kam S, Khodorova A, Montmayeur JP, Strichartz GR. (2011) New perspectives on the endothelin axis in pain. Pharmacol Res, 63 (6): 532-40. [PMID:21352917]
* Clozel M, Maresta A, Humbert M. (2013) Endothelin receptor antagonists. Handb Exp Pharmacol, 218: 199-227. [PMID:24092342]
* Davenport AP. (2002) International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol Rev, 54 (2): 219-26. [PMID:12037137]
* Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, Pollock DM, Webb DJ, Maguire JJ. (2016) Endothelin. Pharmacol Rev, 68 (2): 357-418. [PMID:26956245]
* Davenport AP, Kuc RE, Southan C, Maguire JJ. (2018) New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine. Physiol Res, 67 (Supplementum 1): S37-S54. [PMID:29947527]
Dhaun N, Webb DJ, Kluth DC. (2012) Endothelin-1 and the kidney--beyond BP. Br J Pharmacol, 167 (4): 720-31. [PMID:22670597]
Kohan DE, Cleland JG, Rubin LJ, Theodorescu D, Barton M. (2012) Clinical trials with endothelin receptor antagonists: what went wrong and where can we improve?. Life Sci, 91 (13-14): 528-39. [PMID:22967485]
Kohan DE, Rossi NF, Inscho EW, Pollock DM. (2011) Regulation of blood pressure and salt homeostasis by endothelin. Physiol Rev, 91 (1): 1-77. [PMID:21248162]
Ling L, Maguire JJ, Davenport AP. (2013) Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer. Br J Pharmacol, 168 (2): 283-95. [PMID:22118774]
* Maguire JJ, Davenport AP. (2014) Endothelin@25 - new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12. Br J Pharmacol, 171 (24): 5555-72. [PMID:25131455]
Maguire JJ, Davenport AP. (2015) Endothelin Receptors and Their Antagonists. Semin Nephrol, 35 (2): 125-136. [PMID:25966344]
Nguyen A, Thorin-Trescases N, Thorin E. (2010) Working under pressure: coronary arteries and the endothelin system. Am J Physiol Regul Integr Comp Physiol, 298 (5): R1188-94. [PMID:20237301]
Rubin LJ. (2012) Endothelin receptor antagonists for the treatment of pulmonary artery hypertension. Life Sci, 91 (13-14): 517-21. [PMID:22884806]
Said N, Theodorescu D. (2012) Permissive role of endothelin receptors in tumor metastasis. Life Sci, 91 (13-14): 522-7. [PMID:22846215]
Schneider MP, Boesen EI, Pollock DM. (2007) Contrasting actions of endothelin ET(A) and ET(B) receptors in cardiovascular disease. Annu Rev Pharmacol Toxicol, 47: 731-59. [PMID:17002597]
Schorlemmer A, Matter ML, Shohet RV. (2008) Cardioprotective signaling by endothelin. Trends Cardiovasc Med, 18 (7): 233-9. [PMID:19232951]
Speed JS, Pollock DM. (2013) Endothelin, kidney disease, and hypertension. Hypertension, 61 (6): 1142-5. [PMID:23608655]
Thorin E, Webb DJ. (2010) Endothelium-derived endothelin-1. Pflugers Arch, 459 (6): 951-8. [PMID:19967386]
References
1. Bolli MH, Boss C, Binkert C, Buchmann S, Bur D, Hess P, Iglarz M, Meyer S, Rein J, Rey M et al.. (2012) The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem, 55 (17): 7849-61. [PMID:22862294]
2. Bolli MH, Marfurt J, Grisostomi C, Boss C, Binkert C, Hess P, Treiber A, Thorin E, Morrison K, Buchmann S et al.. (2004) Novel benzo[1,4]diazepin-2-one derivatives as endothelin receptor antagonists. J Med Chem, 47 (11): 2776-95. [PMID:15139756]
3. Breu V, Clozel M, Burri K, Hirth G, Neidhart W, Ramuz H. (1996) In vitro characterisation of Ro 46-8443, the first non-peptide antagonist selective for the endothelin ETB receptor. FEBS Lett, 383 (1-2): 37-41. [PMID:8612786]
4. Clozel M, Breu V, Gray GA, Kalina B, Löffler BM, Burri K, Cassal JM, Hirth G, Müller M, Neidhart W et al.. (1994) Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J Pharmacol Exp Ther, 270 (1): 228-35. [PMID:8035319]
5. Davenport AP. (2002) International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol Rev, 54 (2): 219-26. [PMID:12037137]
6. Davenport AP, Kuc RE, Ashby MJ, Patt WC, Doherty AM. (1998) Characterization of [125I]-PD164333, an ETA selective non-peptide radiolabelled antagonist, in normal and diseased human tissues. Br J Pharmacol, 123 (2): 223-30. [PMID:9489609]
7. Davenport AP, Kuc RE, Fitzgerald F, Maguire JJ, Berryman K, Doherty AM. (1994) [125I]-PD151242: a selective radioligand for human ETA receptors. Br J Pharmacol, 111 (1): 4-6. [PMID:8012722]
8. Elliott JD, Lago MA, Cousins RD, Gao A, Leber JD, Erhard KF, Nambi P, Elshourbagy NA, Kumar C, Lee JA et al.. (1994) 1,3-Diarylindan-2-carboxylic acids, potent and selective non-peptide endothelin receptor antagonists. J Med Chem, 37 (11): 1553-7. [PMID:8201588]
9. Harland SP, Kuc RE, Pickard JD, Davenport AP. (1995) Characterization of endothelin receptors in human brain cortex, gliomas, and meningiomas. J Cardiovasc Pharmacol, 26 Suppl 3: S408-11. [PMID:8587429]
10. Hatae N, Aksentijevich N, Zemkova HW, Kretschmannova K, Tomic M, Stojilkovic SS. (2007) Cloning and functional identification of novel endothelin receptor type A isoforms in pituitary. Mol Endocrinol, 21 (5): 1192-204. [PMID:17312275]
11. Ihara M, Yamanaka R, Ohwaki K, Ozaki S, Fukami T, Ishikawa K, Towers P, Yano M. (1995) [3H]BQ-123, a highly specific and reversible radioligand for the endothelin ETA receptor subtype. Eur J Pharmacol, 274 (1-3): 1-6. [PMID:7768260]
12. Kuc RE, Karet FE, Davenport AP. (1995) Characterization of peptide and nonpeptide antagonists in human kidney. J Cardiovasc Pharmacol, 26 Suppl 3: S373-5. [PMID:8587419]
13. Maguire JJ, Davenport AP. (1995) ETA receptor-mediated constrictor responses to endothelin peptides in human blood vessels in vitro. Br J Pharmacol, 115 (1): 191-7. [PMID:7647976]
14. Mizuguchi T, Nishiyama M, Moroi K, Tanaka H, Saito T, Masuda Y, Masaki T, de Wit D, Yanagisawa M, Kimura S. (1997) Analysis of two pharmacologically predicted endothelin B receptor subtypes by using the endothelin B receptor gene knockout mouse. Br J Pharmacol, 120 (8): 1427-30. [PMID:9113361]
15. Molenaar P, Kuc RE, Davenport AP. (1992) Characterization of two new ETB selective radioligands, [125I]-BQ3020 and [125I]-[Ala1,3,11,15]ET-1 in human heart. Br J Pharmacol, 107 (3): 637-9. [PMID:1472961]
16. Murugesan N, Gu Z, Spergel S, Young M, Chen P, Mathur A, Leith L, Hermsmeier M, Liu EC, Zhang R et al.. (2003) Biphenylsulfonamide endothelin receptor antagonists. 4. Discovery of N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]- 2-yl]methyl]-N,3,3-trimethylbutanamide (BMS-207940), a highly potent and orally active ET(A) selective antagonist. J Med Chem, 46 (1): 125-37. [PMID:12502366]
17. Nambi P, Pullen M, Spielman W. (1994) Species differences in the binding characteristics of [125I]IRL-1620, a potent agonist specific for endothelin-B receptors. J Pharmacol Exp Ther, 268 (1): 202-7. [PMID:8301559]
18. Peter MG, Davenport AP. (1995) Selectivity of [125I]-PD151242 for human, rat and porcine endothelin ETA receptors in the heart. Br J Pharmacol, 114 (2): 297-302. [PMID:7881728]
19. Reynolds EE, Hwang O, Flynn MA, Welch KM, Cody WL, Steinbaugh B, He JX, Chung FZ, Doherty AM. (1995) Pharmacological differences between rat and human endothelin B receptors. Biochem Biophys Res Commun, 209 (2): 506-12. [PMID:7733918]
20. Russell FD, Davenport AP. (1996) Characterization of the binding of endothelin ETB selective ligands in human and rat heart. Br J Pharmacol, 119 (4): 631-6. [PMID:8904635]
21. Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, Masaki T. (1990) Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature, 348 (6303): 732-5. [PMID:2175397]
22. Shihoya W, Izume T, Inoue A, Yamashita K, Kadji FMN, Hirata K, Aoki J, Nishizawa T, Nureki O. (2018) Crystal structures of human ETB receptor provide mechanistic insight into receptor activation and partial activation. Nat Commun, 9 (1): 4711. [PMID:30413709]
23. Shihoya W, Nishizawa T, Yamashita K, Inoue A, Hirata K, Kadji FMN, Okuta A, Tani K, Aoki J, Fujiyoshi Y et al.. (2017) X-ray structures of endothelin ETB receptor bound to clinical antagonist bosentan and its analog. Nat Struct Mol Biol, 24 (9): 758-764. [PMID:28805809]
24. von Geldern TW, Tasker AS, Sorensen BK, Winn M, Szczepankiewicz BG, Dixon DB, Chiou WJ, Wang L, Wessale JL, Adler A et al.. (1999) Pyrrolidine-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ET(B) selectivity. J Med Chem, 42 (18): 3668-78. [PMID:10479298]
25. Watakabe T, Urade Y, Takai M, Umemura I, Okada T. (1992) A reversible radioligand specific for the ETB receptor: [125I]Tyr13-Suc-[Glu9,Ala11,15]-endothelin-1(8- 21), [125I]IRL 1620. Biochem Biophys Res Commun, 185 (3): 867-73. [PMID:1320877]
26. Watanabe T, Awane Y, Ikeda S, Fujiwara S, Kubo K, Kikuchi T, Kusumoto K, Wakimasu M, Fujino M. (1995) Pharmacology of a non-selective ETA and ETB receptor antagonist, TAK-044 and the inhibition of myocardial infarct size in rats. Br J Pharmacol, 114 (5): 949-54. [PMID:7780649]
27. Wu C, Chan MF, Stavros F, Raju B, Okun I, Mong S, Keller KM, Brock T, Kogan TP, Dixon RA. (1997) Discovery of TBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist. J Med Chem, 40 (11): 1690-7. [PMID:9171878]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Anthony P. Davenport (Chairperson)
Pedro D'Orléans-Juste
Théophile Godfraind
Janet J. Maguire
Eliot H. Ohlstein
Robert R. Ruffolo |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SP, Christopoulos A, Davenport AP, Kelly E, Mathie A, Peters JA, Veale EL et al. (2021) THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors. Br J Pharmacol. 176 Suppl 1:S27-S156.
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Splice variants of the ETA receptor have been identified in rat pituitary cells; one of these, ETAR-C13, appeared to show loss of function with comparable plasma membrane expression to wild type receptor [10]. Subtypes of the ETB receptor have been proposed, although gene disruption studies in mice suggest that only a single gene product exists [14]. Crystal structures of the ETB receptor bound to the antagonist bosentan and ETB selective analogue K-8794 [23] and selective ETB agonists endothelin-3 (EDN3, P14138) and IRL 1620 [22] have been reported.