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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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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
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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, 167: 92-96. [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. (2019) Endothelins in cardiovascular biology and therapeutics. Nat Rev Cardiol, 16 (8): 491-502. [PMID:30867577]
Dhaun N, Webb DJ, Kluth DC. (2012) Endothelin-1 and the kidney--beyond BP. Br J Pharmacol, 167 (4): 720-31. [PMID:22670597]
* Ko CJ, Cho YM, Ham E, Cacioppo JA, Park CJ. (2022) Endothelin 2: a key player in ovulation and fertility. Reproduction, 163 (4): R71-R80. [PMID:35167488]
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]
* Tocci P, Blandino G, Bagnato A. (2021) YAP and endothelin-1 signaling: an emerging alliance in cancer. J Exp Clin Cancer Res, 40 (1): 27. [PMID:33422090]
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. Iglarz M, Binkert C, Morrison K, Fischli W, Gatfield J, Treiber A, Weller T, Bolli MH, Boss C, Buchmann S et al.. (2008) Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther, 327 (3): 736-45. [PMID:18780830]
12. 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]
13. Izume T, Miyauchi H, Shihoya W, Nureki O. (2020) Crystal structure of human endothelin ETB receptor in complex with sarafotoxin S6b. Biochem Biophys Res Commun, 528 (2): 383-388. [PMID:32001000]
14. Ji Y, Duan J, Yuan Q, He X, Yang G, Zhu S, Wu K, Hu W, Gao T, Cheng X et al.. (2023) Structural basis of peptide recognition and activation of endothelin receptors. Nat Commun, 14 (1): 1268. [PMID:36882417]
15. Kowala MC, Murugesan N, Tellew J, Carlson K, Monshizadegan H, Ryan C, Gu Z, Kane B, Fadnis L, Baska RA et al.. (2004) Novel dual action AT1 and ETA receptor antagonists reduce blood pressure in experimental hypertension. J Pharmacol Exp Ther, 309 (1): 275-84. [PMID:14718594]
16. 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]
17. 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]
18. Mihara S, Tozawa F, Itazaki K, Fujimoto M. (1998) Binding characterization of [3H]S-0139, an antagonist of the endothelin ET(A) receptor subtype. Eur J Pharmacol, 342 (2-3): 319-24. [PMID:9548403]
19. 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]
20. 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]
21. Morris CD, Rose A, Curwen J, Hughes AM, Wilson DJ, Webb DJ. (2005) Specific inhibition of the endothelin A receptor with ZD4054: clinical and pre-clinical evidence. Br J Cancer, 92 (12): 2148-52. [PMID:15956965]
22. Nagiri C, Shihoya W, Inoue A, Kadji FMN, Aoki J, Nureki O. (2019) Crystal structure of human endothelin ETB receptor in complex with peptide inverse agonist IRL2500. Commun Biol, 2: 236. [PMID:31263780]
23. 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]
24. Opgenorth TJ, Adler AL, Calzadilla SV, Chiou WJ, Dayton BD, Dixon DB, Gehrke LJ, Hernandez L, Magnuson SR, Marsh KC et al.. (1996) Pharmacological characterization of A-127722: an orally active and highly potent ETA-selective receptor antagonist. J Pharmacol Exp Ther, 276 (2): 473-81. [PMID:8632312]
25. 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]
26. Ranjan AK, Gulati A. (2022) Sovateltide Mediated Endothelin B Receptors Agonism and Curbing Neurological Disorders. Int J Mol Sci, 23 (6). [PMID:35328566]
27. 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]
28. Roux S, Breu V, Giller T, Neidhart W, Ramuz H, Coassolo P, Clozel JP, Clozel M. (1997) Ro 61-1790, a new hydrosoluble endothelin antagonist: general pharmacology and effects on experimental cerebral vasospasm. J Pharmacol Exp Ther, 283 (3): 1110-8. [PMID:9399983]
29. 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]
30. 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]
31. 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]
32. Shihoya W, Nishizawa T, Okuta A, Tani K, Dohmae N, Fujiyoshi Y, Nureki O, Doi T. (2016) Activation mechanism of endothelin ETB receptor by endothelin-1. Nature, 537 (7620): 363-368. [PMID:27595334]
33. 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]
34. 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]
35. 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]
36. 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]
37. 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)
Janet J. Maguire |
Other contributors:
George R. Abraham
Thomas L. Williams |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
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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 [19]. Cryogenic-electron microscopy structures of ETA and ETB bound to endothelin-1 (EDN1, P05305) and ETB bound to sovateltide (IRL1620) [14] and crystal structures of the ETB receptor complexed with non-selective agonists endothelin-1 (EDN1, P05305) [32] and sarafotoxin S6b [13], ETB selective agonists endothelin-3 (EDN3, P14138) and sovateltide (IRL1620) [31], inverse agonist IRL 2500 [22], and clinically relevant non-selective antagonist bosentan and the ETB selective analogue K-8794 [33] have been reported. Sparsentan is a combined ETA and AT1 receptor antagonist [15].