Endothelin G Protein-Coupled Receptors

  • Gastone G. Nussdorfer
  • Gian Paolo Rossi
Part of the Endocrine Updates book series (ENDO, volume 17)


Endothelins (ETs) are a family of endogenous peptides, mainly secreted by endothelial cells, which exert a potent vasoconstrictor and pressor activity, acting through two classes of G protein-coupled receptors, called ETa and ETb. ETs were originally isolated from porcine aortic endothelium [1], but subsequent investigations revealed that these peptides are synthesized and their receptors are expressed in a great variety of tissues and organs, where they play important physiological and pathophysiological roles [2–6]. At present, ETs are known to regulate the cardiovascular system and blood pressure (BP), kidney excretion, pulmonary function, endocrine-gland secretion, digestive functions, and the development of tissues derived from embryonic neural-crest lineage and of the central and peripheral nervous systems. The ability of all these tissues to synthesize ETs and the fact that the blood concentrations of ETs are below those able to evoke sizeable biological effects led to the contention that these peptides almost exclusively act through autocrine-paracrine mechanisms.


Granulosa Cell Zona Glomerulosa Coronary Artery Smooth Muscle Cell Human Coronary Artery Smooth Muscle Adrenal Zona Glomerulosa Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Yazaki Y, Goto K, Masaki T. 1988 A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature (London) 332: 411–415.CrossRefGoogle Scholar
  2. 2.
    Rubanyi GM, Polokoff MA. 1994 Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 46: 325–415.PubMedGoogle Scholar
  3. 3.
    Levin ER. 1996 The endothelin peptides. Role in physiology and pathophisiology. In: Sower JR (ed), Endocrinology of the Vasculature. Humana Press, Totowa (NJ), 49–66.CrossRefGoogle Scholar
  4. 4.
    Stojilkovic SS, Catt KJ. 1996 Expression and signal transduction pathways of endothelin receptors in neuroendocrine cells. Front Neuroendocrinol 17: 327–369.CrossRefPubMedGoogle Scholar
  5. 5.
    Miyauchi T, Masaki T. 1999 Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol 61: 391–415.CrossRefPubMedGoogle Scholar
  6. 6.
    Nussdorfer GG, Rossi GP, Malendowicz LK, Mazzocchi G. 1999 Autocrine-paracrine endothelin system in the physiology and pathology of steroid-secreting tissues. Pharmacol Rev 51: 403–437.PubMedGoogle Scholar
  7. 7.
    Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T. 1989 The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA 86: 286–287.CrossRefGoogle Scholar
  8. 8.
    Goto K, Hama H, Kasuya Y. 1996 Molecular pharmacology and pathophysiological significance of endothelin. Jpn J Pharmacol 72: 261–290.CrossRefPubMedGoogle Scholar
  9. 9.
    Malendowicz LK, Macchi V, Brelinska R, Trejter M, Gottardo G, Nussdorfer GG. 1998 Endothelin-1 enhances thymocyte proliferation in monolaterally adrenalectomized rats with controlateral adrenocortical regeneration. Histol Histopathol 13: 721–725.PubMedGoogle Scholar
  10. 10.
    Brock B, Gregersen S, Kristensen K, Thomsen JL, Buschard K, Kofod H, Hermansen K. 1999 The insulinotropic effect of endothelin-1 is mediated by glucagon release from the islet alpha cells. Diabetologia 42: 1302–1307.CrossRefPubMedGoogle Scholar
  11. 11.
    De Carlo E, Milanesi A, Martini C, Maffei P, Sicolo N, Scandellari C. 2000 Endothelin-1 and endothelin-3 stimulate insulin release by isolated rat pancreatic islets. J Endocrinol Invest 23: 240–245.PubMedGoogle Scholar
  12. 12.
    Nakano A, Kishi F, Minami K, Wakabayashi H, Nakaya Y, Kido H. 1997 Selective conversion of big endothelins to tracheal smooth muscle-constricting 31-amino acidlenght endothelins by chymase from human mastcells. J Immunol 159: 1987–1992.PubMedGoogle Scholar
  13. 13.
    Fernandez-Patron C, Radomski MW, Davidge ST. 1999 Vascular matrix metalloproteinase-2 cleaves big endothelin-1 yielding a novel vasoconstrictor. Circ Res 85: 906–911.CrossRefPubMedGoogle Scholar
  14. 14.
    Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. 1990 Cloning and expression of a cDNA encoding an endothelin receptor. Nature (Lond) 348: 730–732.CrossRefGoogle Scholar
  15. 15.
    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 (London) 348: 732–735.CrossRefGoogle Scholar
  16. 16.
    Lin HY, Kaji EH, Winkel GK, Ives HE, Lodish HF. 1991 Cloning and functional expression of vascular smooth muscle endothelin-1 receptor. Proc Natl Acad Sci USA 88: 3185–3189.CrossRefPubMedGoogle Scholar
  17. 17.
    Elshourbagy NA, Adamou JE, Cagnon AW, Wu HL, Pullen M, Nambi P. 1996 Molecular characterization of a novel human endothelin receptor splice variant. J Biol Chem 271: 25300–25307.CrossRefPubMedGoogle Scholar
  18. 18.
    Ohlstein EH, Eliot JD, Feuerstein GZ, Ruffolo RR Jr. 1996 Endothelin receptors: receptor classification, novel receptor antagonists, and potential therapeutic targets. Med Res Rev 16: 365–390.CrossRefPubMedGoogle Scholar
  19. 19.
    Yoshizumi M, Kim S, Kagami S, Hamaguchi A, Tsuchiya K, Houchi H, Iwao H, Kido H, Tamaki T. 1998 Effect of endothelin-1(1–31) on extracellular signal-regulated kinase and proliferation of human coronary artery smooth muscle cells. Br J Pharmacol 125: 1019–1027.CrossRefPubMedGoogle Scholar
  20. 20.
    Yoshizumi M, Inui D, Kirima K, Tsuchiya K, Houchi H, Azuma M, Yasuoka H, Kido H, Tamaki T. 1999 Comparison of the effects of endothelin-1, -2 and -3(1–31) on changes in [Ca2+]i in human coronary artery smooth muscle cells. Jpn J Pharmacol 81: 298–304.CrossRefPubMedGoogle Scholar
  21. 21.
    Galindo-Pacheco Y, Belloni AS, Malendowicz LK, Meneghelli V, Gottardo G, Nussdorfer GG. 1996 Endothelin-1 inhibits renin release by rat kidney acting via the ETA receptor subtype. Biomed Res 17: 429–434.Google Scholar
  22. 22.
    Cartier F, Delarue C, Remy-Jouet I, Kodjo MK, Fournier A, Vaudry H. 1999 The stimulatory effect of endothelin-1 on frog adrenocortical cells is mediated through both the phospholipase C and the adenylate cyclase transduction pathways. Mol Cell Endocrinol 147: 27–36.CrossRefPubMedGoogle Scholar
  23. 23.
    Usuki S, Otani S, Goto K, Sizuki N, Yanagisawa M, Masaki T. 1991 Endothelin induces DNA polymerase-a activity in ovaries of hypophysectomized estrogen-treated immature rats. Horm Metab Res 26: 621–622.CrossRefGoogle Scholar
  24. 24.
    Flores JA, Quyyumi S, Leong DA, Veldhuis JD. 1992 Actions of endothelin-1 on swine ovarian (granulosa) cells. Endocrinology 131: 1350–1358.CrossRefPubMedGoogle Scholar
  25. 25.
    Tedeschi C, Lohman C, Hazum E, Ittoop O, Ben-Shlomo I, Resnick CE, Payne DW, Adashi EY. 1994 Rat ovarian granulosa cell as a site of endothelin reception and action: attenuation of gonadotropin-stimulated steroidogenesis via perturbation of the A-kinase signaling pathway. Biol Reprod 51: 1058–1065.CrossRefPubMedGoogle Scholar
  26. 26.
    Calogero AE, Burrello N, Ossino AM. 1998 Endothelin (ET)-1 and ET-3 inhibit estrogen and cAMP production by rat granulosa cells in vitro. J Endocrinol 157: 209–215.CrossRefPubMedGoogle Scholar
  27. 27.
    Rossi GP, Belloni AS, Colonna S, Nussdorfer GG, Pessina AC. 1998 Endothelin receptor subtypes in human arterial hypertension. J Hypertens 16: S81 - S84.Google Scholar
  28. 28.
    Rossi GP, Andreis PG, Neri G, Tortorella C, Pelizzo MR, Sacchetto A, Nussdorfer GG. 2000 Endothelin-1 stimulates aldosterone synthesis in Conn’s adenomas via both A and B receptors coupled with the protein kinase C- and cyclooxygenase-dependent signaling pathways. J Investig Med 48: 335–342.Google Scholar
  29. 29.
    Andreis PG, Tortorella C, Malendowicz LK, Nussdorfer GG. 2001 Endothelins stimulate aldosterone secretion from dispersed rat adrenal zona glomerulosa cells, acting through ETB receptors coupled with the phospholipase C-dependent signaling pathway. Peptides, 22: 117–122.CrossRefPubMedGoogle Scholar
  30. 30.
    Garrido MR, Israel A. 1997 Endothelin ETA receptor subtype mediates phosphoinositide hydrolysis in adrenal medulla. Arch Physiol Biochem 105: 467–472.CrossRefPubMedGoogle Scholar
  31. 31.
    Kamada S, Blackmore PF, Kubota T, Oehninger S, Asada Y, Gordon K, Hodgen GD, Aso T. 1995 The role of endothelin-1 in regulating human granulosa cell proliferation and steroidogenesis in vitro. J Clin Endocrinol Metab 80: 3708–3714.CrossRefPubMedGoogle Scholar
  32. 32.
    Tanini A, Failli P, Maggi M, Franceschelli F, Frediani U, Becherini L, Giotti A, Ruocco C, Brandi ML. 1993 Effects of endothelin-1 on bovine parathyroid cells. Biochem Biophys Res Commun 193: 59–66.CrossRefPubMedGoogle Scholar
  33. 33.
    Fujii Y, Tomic M, Stojilkovic SS, Iida T, Brandi ML, Ogino Y, Sakaguchi K. 1995 Effects of endothelin-1 on Cat+ signaling and secretion in parathyroid cells. J Bone Mineral Res 10: 716–725.CrossRefGoogle Scholar
  34. 34.
    Romanelli F, Fillo S, Isidori A, Conte D. 1997 Stimulatory action of endothelin-1 on rat Leydig cells: involvement of endothelin-A subtype receptor and phospholipase A2arachidonate metabolism system. Life Sci 61: 557–566.CrossRefPubMedGoogle Scholar
  35. 35.
    Girsh E, Milvae RA, Wang W, Meidan R. 1996 Effect of endothelin-1 on bovine luteal cell function: role of prostaglandin Fla-induced antisteroidogenic action. Endocrinology 137: 1306–1312.CrossRefPubMedGoogle Scholar
  36. 36.
    Acosta TJ, Miyamoto A, Ozawa T, Wijayagunawardane MP, Sato K. 1998 Local release of steroid hormones, prostaglandin E2 and endothelin-1 from bovine mature follicles in vitro: effects of luteinizing hormone, endothelin-1, and cytokines. Biol Reprod 59: 437–443.CrossRefPubMedGoogle Scholar
  37. 37.
    Meidan R, Girsch E. 1997 Role of endothelial cells in the steroidogenic activity of the bovine corpus luteum. Semin Reprod Endocrinol 15: 371–382.CrossRefPubMedGoogle Scholar
  38. 38.
    Ohtani M, Kobayashi SI, Miyamoto A, Hayashi K, Fukui Y. 1998 Real-time relationships between intraluteal and plasma concentrations of endothelin, oxytocin, and progesterone during prostaglandin Fla-induced luteolysis in the cow. Biol Reprod 58: 103–108.CrossRefPubMedGoogle Scholar
  39. 39.
    Brown MA, Smith PL. 1991 Endothelin: a potent stimulator of intestinal ion secretion in vitro. Regul Pept 36: 1–19.CrossRefPubMedGoogle Scholar
  40. 40.
    Exton JH. 1997 Phospholipase D: enzymology, mechanisms of regulation, and function. Physiol Rev 77: 303–320.PubMedGoogle Scholar
  41. 41.
    Zhang Y, Abdel-Latif AA. 1992 Activation of phospholipase D by endothelin-1 and other pharmacological agents in rabbit iris sphincter smooth muscle. Cell Signal 4: 777786.Google Scholar
  42. 42.
    Naze S, Le Stunff H, Dokhac L, Thomas G, Harbon S. 1997 Activation of phospholipase D by endothelin-1 in rat myometrium. Role of calcium and protein kinase C. J Pharmacol Exp Ther 281: 15–23.Google Scholar
  43. 43.
    Clerk A, Sugden PH. 1997 Regulation of phospholipases C and D in rat ventricular myocytes: stimulation by endothelin-1, bradykinin and phenylephrine. J Mol Cell Cardiol 29: 1593–1604.CrossRefPubMedGoogle Scholar
  44. 44.
    Desagher S, Cordier J, Glowinski J, Tence M. 1997 Endothelin stimulates phospholipase D in striatal astrocytes. J Neurochem 68: 78–87.CrossRefPubMedGoogle Scholar
  45. 45.
    Servitja JM, Masgrau R, Sarri E, Picatoste F. 1998 Involvement of ETA and ETB receptors in the activation of phospholipase D by endothelins in cultured rat cortical astrocytes. Br J Pharmacol 124: 1728–1734.CrossRefPubMedGoogle Scholar
  46. 46.
    Kester M, Simonson MS, McDermott RG, Baldi E, Dunn MJ. 1992 Endothelin stimulates phosphatidic acid formation in cultured rat mesangial cells: role of protein kinase C-regulated phospholipase D. J Cell Physiol 150: 578–585.CrossRefPubMedGoogle Scholar
  47. 47.
    Peed A, Romero DG, Lantos C, Cozza EN. 1998 Mechanisms of action of endothelin1 in rat adrenal. Life Sci 63: 1315–1328.CrossRefGoogle Scholar
  48. 48.
    Campbell JS, Seger R, Graves JD, Jensen AM, Krebs EG. 1995 The MAP kinase cascade. Recent Prog Horm Res 50: 131–159.PubMedGoogle Scholar
  49. 49.
    Fanger GR. 1999 Regulation of the MAPK family members: role of subcellular localization and architectural organization. Histol Histopathol 14: 887–894.PubMedGoogle Scholar
  50. 50.
    Blumer KJ, Johnson GL. 1994 Diversity in function and regulation of MAP kinase pathway. Trends Biochem Sci 19: 236–240.CrossRefPubMedGoogle Scholar
  51. 51.
    Wang Y, Rose PM, Webb ML, Dunn MJ. 1994 Endothelins stimulate mitogenactivated protein kinase cascade through either ETA or ETB. Am J Physiol 267:C1130-C 1135.Google Scholar
  52. 52.
    Biesen TV, Luttrell LM, Hawes BE, Lefkowitz RJ. 1996 Mitogenic signaling via G protein-coupled receptors. Endocr Rev 17: 698–714.CrossRefPubMedGoogle Scholar
  53. 53.
    Takigawa M, Sakurai T, Kasuya Y, Abe Y, Masaki T, Goto K. 1995 Molecular characterization of guanine-nucleotide-binding regulatory proteins which couple to endothelin receptors. Eur J Biochem 228: 102–108.CrossRefPubMedGoogle Scholar
  54. 54.
    Mazzocchi G, Rossi GP, Rebuffat P, Malendowicz LK, Markowska A, Nussdorfer GG. 1997 Endothelins stimulate deoxyribonucleic acid synthesis and cell proliferation in rat adrenal zona glomerulosa, acting through an endothelin A receptor coupled with protein kinase C- and tyrosine kinase-dependent signaling pathways. Endocrinology 138: 2333–2337.CrossRefPubMedGoogle Scholar
  55. 55.
    Andrew PG, Mayer B. 1999 Enzymatic functions of nitric oxide synthases. Cardiovasc Res 43: 521–531.CrossRefPubMedGoogle Scholar
  56. 56.
    Li H, Föstermann U. 2000 Nitric oxide in the pathogenesis of vascular disease. J Pathol 190: 244–254.CrossRefPubMedGoogle Scholar
  57. 57.
    Goligorsky MS, Tsukahara H, Magazine H, Andersen TT, Malik AB, Bahou WF. 1994 Termination of endothelin signaling: role of NO. J Cell Physiol 158: 485–494.CrossRefPubMedGoogle Scholar
  58. 58.
    Mazzocchi G, Malendowicz LK, Musajo FG, Gottardo G, Markowska A, Nussdorfer GG. 1998 The role of endothelins in the regulation of vascular tone in the in situ perfused rat adrenals. Am J Physiol 274: E1 - E5.PubMedGoogle Scholar
  59. 59.
    Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC. 1998 Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest 101: 731–736.CrossRefPubMedGoogle Scholar
  60. 60.
    Weyer RM, Luscher TF, Cosentino F, Rabelink TJ. 1998 Atherosclerosis and the two faces of endothelial nitric oxide synthase. Circulation 97: 108–112.CrossRefGoogle Scholar
  61. 61.
    Puffenberger EG, Hosoda K, Washington SS, Nakao K, de Witt D, Yanagisawa M, Chakravarti A. 1994 A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung’s disease. Cell 79: 1257–1266.CrossRefPubMedGoogle Scholar
  62. 62.
    Hosoda K, Hammer RE, Richardson JA, Baynash AG, Cheung JC, Giaid A, Yanagisawa M. 1994 Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 79: 1267–1276.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Gastone G. Nussdorfer
    • 1
  • Gian Paolo Rossi
    • 2
  1. 1.Departments of Human Anatomy and PhysiologyUniversity of PaduaPaduaItaly
  2. 2.Clinical and Experimental Medicine, School of MedicineUniversity of PaduaPaduaItaly

Personalised recommendations