Endothelin pp 31-73 | Cite as

Molecular Biology of the Endothelin Receptors

  • Jonathan A. Lee
  • Eliot H. Ohlstein
  • Catherine E. Peishoff
  • John D. Elliott
Part of the Contemporary Biomedicine book series (CB)


Since the initial discovery of the endothelium-derived constricting factor, endothelin-1 (ET-1) (1) and determination of its peptidic nature (2), elucidation of the molecular details of the endothelin (ET) system has progressed rapidly via a multidisciplinary approach using the tools of biochemistry, chemistry, pharmacology, and molecular biology. Milestones in the development of this area include the isolation (3) and three-dimensional structure determination (4,5) of ET-1 and related peptides, the pharmacological characterization and molecular cloning of ET-receptor subtypes (6,7) which was followed by the development of potent peptide and nonpeptide antagonists (8–13), and, more recently, the disruption of the genes encoding ET-1, ET-3, and the ETB receptor subtype (14–16). Thus elucidation of the intricacies of the endothelin system has been the product of a truly molecular approach to pharmacology.


Receptor mRNA Thyrotropin Release Hormone Carboxyl Terminus Region Receptor Residue Nonpeptide Ligand 
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.
    Hickey, K. A., Rubanyi, G., Paul, R. J., and Highsmith, R. F. (1985) Characterization of a coronary vasoconstrictor produced by cultured endothelial cells. Am. J. Physiol. 248: C550–0556.PubMedGoogle Scholar
  2. 2.
    Gillespie, M. N., Owsaoyo, J. O., McMurtry, I. F., and O’Brien, R. F. (1986) Sustained coronary vasoconstriction provoked by a peptidergic substance from endothelial cell culture. J. Pharm. Exp. Ther. 236: 339–343.Google Scholar
  3. 3.
    Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., Mitsui, Y., Yazaki, Y., Goto, K., and Masaki, T. A. (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411–415.PubMedCrossRefGoogle Scholar
  4. 4.
    Janes, R. W., Peapus, D. H., and Wallace, B. A. (1994) The crystal structure of human endothelin. Nature Struct. Biol. 1: 311–319.PubMedCrossRefGoogle Scholar
  5. 5.
    Andersen, N. H., Chen, C., Marschner, T. M., Stanley R. Krystek, J., and Bassolino, D. A. (1992) Conformational isomerism of endothelin in acidic aqueous media: a quantitative NOESY analysis. Biochemistry 31: 1280–1295.PubMedCrossRefGoogle Scholar
  6. 6.
    Arai, H., Hori, S., Aramori, I., Ohkubo, H., and Nakanishi, S. (1990) Cloning and expression of a cDNA encoding an endothelin receptor. Nature 348: 730–732.PubMedCrossRefGoogle Scholar
  7. 7.
    Sakurai, T., Yanagisawa, M., Takuwa, Y., Miyazaki, H., Kimura, S., Goto, K., and Masaki, T. (1990) Cloning of a cDNA encoding a non-isopeptideselective subtype of the endothelin receptor. Nature 348: 732–735.PubMedCrossRefGoogle Scholar
  8. 8.
    Ihara, M., Noguchi, K., Saeki, T., Fururoda, T., Tsuchida, S., Kimura, S., Fukami, T. R., Ishikawa, K., Nishikibe, M., and Yano, M. (1991) Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor. Life Sci. 50: 247–255.CrossRefGoogle Scholar
  9. 9.
    Clozel, M., Breu, V., Burri, K., Cassal, J. M., Fischli, W., Hirth, G., Loffler, B. M., Muller, M., Neidhart, W., and Ramuz, H. (1993) Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature 365: 759–761.PubMedCrossRefGoogle Scholar
  10. 10.
    Elliott, J. D., A. M., L., Cousins, R. D., Gao, A., Leber, J. D., Erhard, K. F., Nambi, P., Elshourbagy, N. Y., Kumar, C., Lee, J. A., Bean, J. W., DeBrosse, C. F., Eggleston, D. S., Brooks, D. P., Feuerstein, G., Ruffolo, R. R., Weinstock, J., Gleason, J. G., Peishoff, C. E., and Ohlstein, E. H. (1994) 1,3-Diarylindane-2-carboxylic acids, potent and selective non-peptide endothelin receptor antagonists. J. Med. Chem. 37: 1553–1557.Google Scholar
  11. 11.
    Ohlstein, E. H., Nambi, P., Douglas, S. A., Edwards, R. M., Gellai, M., Lago, A., Leber, J. D., Cousins, R. D., Gao, A., Frazee, J. S., Peishoff, C. E., Bean, J. W., Eggleston, D., Elshourbagy, N., Kumar, C., Lee, J. A., Yue, T.-L., Louden, C., Brooks, D. P., Weinstock, J., Feuerstein, G., Poste, G., R. R. Ruffalo, J., Gleason, J. G., and Elliott, J. D. (1994) SB 209670, A rationally designed potent nonpeptide endothelin receptor antagonist. Proc. Natl. Acad. Sci. USA 91: 8052–8056.PubMedCrossRefGoogle Scholar
  12. 12.
    Roux, S. P. C. M., Sprecher, U., Gray, G., and Clozel, J. P. (1993) Ro 47–0203, A new endothelin receptor antagonist reverses chronic vasospasm in experimental subarachnoid hemorrahage. Circulation 88: I170.Google Scholar
  13. 13.
    Stein, P. D., Hunt, J. T., Floyd, D. M., Moreland, S., Dickinson, K. E. J., Mitchell, C., Liu, E. C.-K., Webb, M. L. M., N., Dickey, J., McMullen, D., Zhang, R., Lee, V. G., Serafino, R., Delaney, C., Schaeffer, T. R., and Kozlowski, M. (1994) The discovery of sulfonamide endothelin antagonists and the development of the orally active ETA antagonist 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide. J. Med. Chem. 37: 329–331.PubMedCrossRefGoogle Scholar
  14. 14.
    Baynash, A. G., Hosoda, K., Giaid, A., Richardson, J. A., Emoto, N., Hammer, R. E., and Yanagisawa, M. (1994) Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79: 1277–1285.PubMedCrossRefGoogle Scholar
  15. 15.
    Hosoda, K., Hammer, R. E., Richardson, J. A., Baynash, A. G., Cheung, J. C., Giaid, A., and 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.PubMedCrossRefGoogle Scholar
  16. 16.
    Kurihara, Y., Kurihara, H., Suzuki, H., Kodama, T., Maemura, K., Nagai, R., Oda, H., Kuwaki, T., Cao, W. H., Kamada, N., et al. (1994) Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature 368: 703–710.PubMedCrossRefGoogle Scholar
  17. 17.
    Probst, W. C., Snyder, L. A., Schuster, D. I., Brosius, J., and Sealfon, S. C. (1992) Sequence alignment of the G-protein coupled receptor super-family. DNA Cell Biol. 11, 1–20.PubMedCrossRefGoogle Scholar
  18. 18.
    Takayanagi, R., Ohnaka, K., Takasaki, C., Ohashi, M., and Nawata, H. (1991) Multiple subtypes of endothelin receptors in porcine tissues: characterization by ligand binding, affinity labeling and regional distribution. Regul. Peps. 32: 23–37.CrossRefGoogle Scholar
  19. 19.
    Bax, W. A. and Saxena, P. R. (1994) The current endothelin receptor classification: time for reconsideration? Trends Pharmacol. Sci. 15: 379–386.PubMedCrossRefGoogle Scholar
  20. 20.
    Sokolovsky, M. (1992) Structure-function relationships of endothelins, sarafotoxins, and their receptor subtypes. J. Neurochem. 59: 809–821.PubMedCrossRefGoogle Scholar
  21. 21.
    Takai, M., Umemura, I., Yamasaki, K., Watakabe, T., Fujitani, Y., Oda, K., Urade, Y., Inui, T., Yamamura, T., and Okada, T. (1992) A potent and specific agonist, Suc-[G1u9,A1a11,15]-endothelin-1(8–21), IRL 1620, for the ETB receptor. Biochem. Biophys. Res. Comm. 184: 953–959.PubMedCrossRefGoogle Scholar
  22. 22.
    Arai, H., Nakao, K., Takaya, K., Hosoda, K., Ogawa, Y., Nakanishi, S., and Imura, H. (1993) The human endothelin-B receptor gene. Structural organization and chromosomal assignment. J. Biol. Chem. 268: 34633470.Google Scholar
  23. 23.
    Cheng, H. F., Su, Y. M., Yeh, J. R., and Chang, K. J. (1993) Alternative transcript of the nonselective-type endothelin receptor from rat brain. Mol. Pharm. 44: 533–538.Google Scholar
  24. 24.
    Hosoda, K., Nakao, K., Tamura, N., Arai, H., Ogawa, Y., Suga, S., Nakanishi, S., and Imura, H. (1992) Organization, structure, chromosomal assignment, and expression of the gene encoding the human endothelinA receptor. J. Biol. Chem. 267:18, 797–18, 804.Google Scholar
  25. 25.
    Mizuno, T., Saito, Y., Itakura, M., Ito, F., Ito, T., Moriyama, N., Hagiwara, H., and Hirose, S. (1992) Structure of the bovine ETB receptor gene. Biochem. J. 287: 305–309.PubMedGoogle Scholar
  26. 26.
    Shyamala, V., Moulthrop, T. H. M., Stratton-Thomas, J., and TekampOlson, P. (1994) Two distinct human endothelin b receptors generated by alternate splicing from a single gene. Cell. Mol. Biol. Res. 40: 285–296.PubMedGoogle Scholar
  27. 27.
    Breathnach, R. and Chambon, P. (1981) Organization and expression of eukaryotic split genes coding for proteins. Ann. Rev. Biochem. 50: 349–383.PubMedCrossRefGoogle Scholar
  28. 28.
    Maniatis, T., Goodbourn, S., and Fischer, J. A. (1987) Regulation of inducible and tissue-specific gene expression. Science 23: 1237–1245.CrossRefGoogle Scholar
  29. 29.
    Kadonaga, J. T., Jones, K. A., and Tijan, R. (1986) Promoter-specific activation of RNA polymerase II transcription by Sp 1. Trends Biochem. Sci. 11: 20–23.CrossRefGoogle Scholar
  30. 30.
    Fowlkes, D. M., Mullis, N. T., Comeau, C. M., and Crabtree, G. R. (1984) Potential basis for regulation of the coordinately expressed fibrinogen genes: homology in the 5’ flanking regions. Proc. Natl. Acad. Sci. USA 81: 2313–2316.PubMedCrossRefGoogle Scholar
  31. 31.
    Murre, C., McCaw, P. S., Vaessin, H., Caudy, M., Jan, L. Y., Jan, Y. N., Cabrera, C. V., Buskin, J. N., Hauschka, S. D., Lassar, A. B., et al. (1989) Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell 58: 537–544.PubMedCrossRefGoogle Scholar
  32. 32.
    Bergsma, D. J., Elshourbagy, N., and Kumar, C. (1995) Molecular biology of endothelin receptors, in Endothelin Receptors from the Gene to the Human ( Ruffolo, R. R., ed.), CRC, Boca Raton, FL, pp. 37–58.Google Scholar
  33. 33.
    Goto, K. and Warner, T. D. (1995) Endothelin versatility. Nature 375: 539–540.PubMedCrossRefGoogle Scholar
  34. 34.
    Puffenberger, E. G., Hosoda, K., Washington, S. S., Nakao, K., deWit, D., Yanagisawa, M., and Chakravart, A. (1994) A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung’s disease. Cell 79: 1257–1266.PubMedCrossRefGoogle Scholar
  35. 35.
    Hosoda, K., Nakao, K., Hiroshi, A., Suga, S., Ogawa, Y., Mukoyama, M., Shirakami, G., Saito, Y., Nakanishi, S., and Imura, H. (1991) Cloning and expression of human endothelin-1 receptor eDNA. FEBS Letts. 287: 23–26.CrossRefGoogle Scholar
  36. 36.
    Ogawa, Y., Nakao, K., Arai, H., Nakagawa, O., Hosoda, K., Suga, S., Nakanishi, S., and Imura, H. (1991) Molecular cloning of a nonisopeptide-selective human endothelin receptor. Biochem. Biophys. Res. Comm. 178: 248–255.PubMedCrossRefGoogle Scholar
  37. 37.
    Davenport, A. P., O’Reilly, G., and Kuc, R. E. (1995) Endothelin ETA and ETB mRNA and receptors expressed by smooth muscle in the human vasculature: majority of the ETA sub-type. Brit. J. Pharmacol. 114: 1110–1116.CrossRefGoogle Scholar
  38. 38.
    Brooks, D. P., DePalma, P. D., Pullen, M., and Nambi, P. (1994) Characterization of canine renal endothelin receptor subtypes and their function. J. Pharmacol. Exp. Ther. 268: 1091–1097.PubMedGoogle Scholar
  39. 39.
    Gellai, M., DeWolf, R., Pullen, M., and Nambi, P. (1994) Distribution and functional role of renal ET receptor subtypes in normotensive and hypertensive rats. Kid. Int. 46: 1287–1294.CrossRefGoogle Scholar
  40. 40.
    Telemaque, S., Gratton, J. P., Claing, A., and D’Orleans-Juste, P. (1993) Endothelin-1 induces vasoconstriction and prostacyclin release via the activation of endothelin ETA receptors in the perfused rabbit kidney. Eur. J. Pharmacol. 237: 275–281.PubMedCrossRefGoogle Scholar
  41. 41.
    Terada, Y., Tomita, K., Nonoguchi, H., and Marumo, F. (1992) Different localization of two types of endothelin receptor mRNA in microdissected rat nephron segments using reverse transcription and polymerase chain reaction assay. J. Clin. Invest. 90: 107–112.PubMedCrossRefGoogle Scholar
  42. 42.
    Kohan, D. E., Hughes, A. K., and Perkins, S. L. (1992) Characterization of endothelin receptors in the inner medullary collecting duct of the rat. J. Biol. Chem. 267:12, 336–12, 340.Google Scholar
  43. 43.
    Hasegawa, K., Fujiwara, H., Doyama, K., Inada, T., Ohtani, S., Fujiwara, T., Hosoda, K., Nakao, K., and Sasayama, S. (1994) Endothelin-1-selective receptor in the arterial intima of patients with hypertension. Hypertension 23: 288–293.PubMedCrossRefGoogle Scholar
  44. 44.
    Wang, X., Douglas, S. A., and Ohlstein, E. H. (1996) The use of quantitative RT-PCR to demonstrate the increased expression of endothelinrelated mRNA’s following angioplasty-induced neointima formation in the rat. Circ. Res. 78: 322–328.PubMedCrossRefGoogle Scholar
  45. 45.
    Elshourbagy, N. A., Korman, D. R., Wu, H. L., Sylvester, D. R., Lee, J. A., Nuthalanganti, P., Bergsma, D. J., Kumar, C. S., and Nambi, P. (1993) Molecular characterization and regulation of the human endothelin receptors. J. Biol. Chem. 268: 3873.PubMedGoogle Scholar
  46. 46.
    Dashwood, M. R., Allen, S. P., Luu, T. N., and Muddle, J. R. (1994) The effect of the ETA receptor antagonist, FR 139317, on [125I]-ET-1 binding to the atherosclerotic human coronary artery. Brit. J. Pharmacol. 112: 386–389.CrossRefGoogle Scholar
  47. 47.
    Li, H., Chen, S. J., Chen, Y. F., Meng, Q. C., Durand, J., Oparil, S., and Elton, T. S. (1994) Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. J. Appl. Physiol. 77: 1451–1459.PubMedGoogle Scholar
  48. 48.
    Li, H., Elton, T. S., Chen, Y. F., and Oparil, S. (1994) Increased endothelin receptor gene expression in hypoxic rat lung. Am. J. Phys. 266: 553–560.Google Scholar
  49. 49.
    Takeda, M., Iwasaki, S., Hellings, S. E., Yoshida, H., Homma, T. and Kon, V. (1994) Divergent expression of ETA and ETB receptors in response to cyclosporine in mesangial cells. Am. J. Pathol. 144: 473.PubMedGoogle Scholar
  50. 50.
    Nakamura, T., Ebihara, I., Fukui, M., Osada, S., Tomino, Y., Masaki, T., Goto, K., Furuichi, Y., and Koide, H. (1995) Modulation of glomerular endothelin and endothelin receptor gene expression in aminonucleoside-induced nephrosis. J. Am. Soc. Nephrol. 5: 1585–1590.PubMedGoogle Scholar
  51. 51.
    Nakamura, T., Ebihara, I., Fukui, M., Osada, S., Tomino, Y., Masaki, T., Goto, K., Furuichi, Y., and Koide, H. (1993) Renal expression of mRNAs for endothelin-1, endothelin-3 and endothelin receptors in NZB/ W F1 mice. Renal Phys. Biochem. 16: 233–243.Google Scholar
  52. 52.
    Nambi, P., Pullen, M., Wu, H. L., Nuthulaganti, P., Elshourbagy, N., and Kumar, C. (1992) Dexamethasone down-regulates the expression of endothelin receptors in vascular smooth muscle cells. J. Biol. Chem. 267:19, 555–19, 559.Google Scholar
  53. 53.
    Elshourbagy, N. A., Lee, J. A., Korman, D. R., Nuthalaganti, P., Sylvester, D. R., Dilella, A. G., Sutiphong, J. A., and Kumar, C. S. (1992) Molecular cloning and characterization of the major endothelin receptor subtype in porcine cerebellum. Mol. Pharm. 41: 465–473.Google Scholar
  54. 54.
    Lin, H. Y., Kaji, E. H., Winkel, G. K., Ives, H. E., and Lodish, H. F. (1991) Cloning and functional expression of a vascular smooth muscle endothelin 1 receptor. Proc. Natl. Acad. Sci. USA 88: 3185–3189.PubMedCrossRefGoogle Scholar
  55. 55.
    Saito, Y., Mizuno, T., Itakura, M., Suzuki, Y., Ito, T., Hagiwara, H., and Hirose, S. (1991) Primary structure of bovine endothelin ETB receptor and identification of signal peptidase and metal proteinase cleavage sites. J. Biol. Chem. 266:23, 433–23, 437.Google Scholar
  56. 56.
    Adachi, M., Yang, Y. Y., Furuichi, Y., and Miyamoto, C. (1991) Cloning and characterization of cDNA encoding human A-type endothelin receptor. Biochem. Biophys. Res. Comm. 180: 1265–1272.PubMedCrossRefGoogle Scholar
  57. 57.
    Nakamuta, M., Takayanagi, R., Sakai, Y., Sakamoto, S., Hagiwara, H., Mizuno, T., Saito, Y., Hirose, S., Yamamoto, M., and Nawata, H. (1991) Cloning and sequence analysis of a cDNA encoding human non-selective type of endothelin receptor. Biochem. Biophys. Res. Comm. 177: 34–39.PubMedCrossRefGoogle Scholar
  58. 58.
    Ogawa, Y., Nakao, K., Arai, H., Nakagawa, O., Hosoda, K., Suga, S., Nakanishi, S., and Imura, H. (1991) Molecular cloning of a nonisopeptide-selective human endothelin receptor. Biochem. Biophys. Res. Comm. 178: 248–255.PubMedCrossRefGoogle Scholar
  59. 59.
    Sakamoto, A., Yanagisawa, M., Sakurai, T., Takuwa, Y., Yanagisawa, H., and Masaki, T. (1991) Cloning and functional expression of human cDNA for the ETB endothelin receptor. Biochem. Biophys. Res. Comm. 178: 656–663.PubMedCrossRefGoogle Scholar
  60. 60.
    Kumar, C., Mwangi, V., Nuthulaganti, P., Wu, H. L., Pullen, M., Brun, K., Aiyar, H., Morris, R. A., Naughton, R., and Nambi, P. (1994) Cloning and characterization of a novel endothelin receptor from Xenopus heart. J. Biol. Chem. 269:13, 414–13, 420.Google Scholar
  61. 61.
    Karne, S., Jayawickreme, C. K., and Lerner, M. R. (1993) Cloning and characterization of an endothelin-3 specific receptor (ETC receptor) from Xenopus laevis dermal melanophores. J. Biol. Chem. 268:19, 126–19, 133.Google Scholar
  62. 62.
    Dohlman, H. G., Bouvier, M., Benovic, J. L., Caron, M. G., and Lefkowitz, R. J. (1987) The multiple membrane spanning topography of the ß2-adrenergic receptor. Localization of the sites of binding, glycosylation, and regulatory phosphorylation by limited proteolysis. J. Biol. Chem. 262:14, 282–14, 288.Google Scholar
  63. 63.
    Wang, H., Lipfert, L., Malbon, C. C., and Bahouth, S. (1989) Site-directed anti-peptide antibodies define the topography of the beta-adrenergic receptor. J. Biol. Chem. 264:14, 424–4, 431.Google Scholar
  64. 64.
    O’Dowd, B. F., Hnatowich, M., Regan, J. W., Leader, W. M., Caron, M. G., Lefkowitz, R. J., and Bouvier, M. (1989) Palmitoylation of the human b2-adrenergic receptor. J. Biol. Chem. 264: 7564–7569.Google Scholar
  65. 65.
    Ovchinnikov, Y. A., Abdulaev, N. G., and Bogachuk, A. S. (1988) Two adjacent cysteine residues in the C-terminal cytoplasmic fragment of bovine rhodopsin are palmitylated. FEBS Letts. 254: 89–93.Google Scholar
  66. 66.
    Haendler, B., Hechler, U., Becker, A., and Schleuning, W. D. (1993) Extracellular cysteine residues 174 and 255 are essential for active expression of human endothelin receptor ETB in Escherichia coli. J. Cardiovas. Pharmacol. 22: 54–56.CrossRefGoogle Scholar
  67. 67.
    Nambi, P., Kumar, C., and Ohlstein, E. H. (1995) Signal transduction processes involved in endothelin-mediated responses, in Endothelin Receptors from the Gene to the Human ( Ruffolo, R. R., ed.), CRC, Boca Raton, FL, pp. 59–78.Google Scholar
  68. 68.
    Aramori, I. and Nakanishi, S. (1992) Coupling of two endothelin receptor subtypes to differing signal transduction in transfected Chinese hamster ovary cells. J. Biol. Chem. 267:12, 468–12, 474.Google Scholar
  69. 69.
    Takagi, Y., Ninomiya, H., Sakamoto, A., Miwa, S., and Masaki, T. (1995) Structural basis of G protein specificity of human endothelin receptors. A study with endothelinA/B chimeras. J. Biol. Chem. 270:10, 072–10, 078.Google Scholar
  70. 70.
    Hashido, K., Adachi, M., Gamou, T., Wantanabe, T., Furuichi, Y., and Miyamoto, C. (1993) Identification of specific intracellular domains of the human eta receptor required for ligand binding and signal transduction. Cell. Mol. Biol. Res. 39, 3–12.PubMedGoogle Scholar
  71. 71.
    Fraser, C. M., Chung, F. Z., Wang, C. D., and Venter, J. C. (1988) Site-directed mutagenesis of human beta-adrenergic receptors: substitution of aspartic acid-130 by asparagine produces a receptor with high-affinity agonist binding that is uncoupled from adenylate cyclase. Proc. Natl. Acad. Sci. USA 85, 5478–5482.PubMedCrossRefGoogle Scholar
  72. 72.
    Fraser, C. M., Wang, C. D., Robinson, D. A., Gocayne, J. D., and Venter, J. C. (1989) Site-directed mutagenesis of ml muscarinic acetylcholine receptors: conserved aspartic acids play important roles in receptor function. Mol. Pharm. 36: 840–847.Google Scholar
  73. 73.
    Nussenzveig, D. R., Thaw, C. N., and Gershengorn, M. C. (1994) Inhibition of inositol phosphate second messenger formation by intracellular loop one of a human calcitonin receptor. Expression and mutational analysis of synthetic receptor genes. J. Biol. Chem. 269:28, 123–28, 129.Google Scholar
  74. 74.
    Nussenzveig, D. R., Mathew, S., and Gershengorn, M. C. (1995) Alternative splicing of a 48-nucleotide exon generates two isoforms of the human calcitonin receptor. Endocrinology 136: 2047–2051.PubMedCrossRefGoogle Scholar
  75. 75.
    Senogles, S. E. (1994) The D2 dopamine receptor isoforms signal through distinct Gi alpha proteins to inhibit adenylyl cyclase. A study with site-directed mutant Gi alpha proteins. J. Biol. Chem. 269:23, 120–23, 127.Google Scholar
  76. 76.
    Spengler, D., Waeber, C., Pantaloni, C., Holsboer, F., Bockaert, J., Seeburg, P. H., and Journot, L. (1993) Differential signal transduction by five splice variants of the PACAP receptor. Nature 365: 170–175.PubMedCrossRefGoogle Scholar
  77. 77.
    Vanetti, M., Vogt, G., and Hollt, V. (1993) The two isoforms of the mouse somatostatin receptor (mSSTR2A and mSSTR2B) differ in coupling efficiency to adenylate cyclase and in agonist-induced receptor desensitization. FEBS Letts. 331: 260–266.CrossRefGoogle Scholar
  78. 78.
    Namba, T., Sugimoto, Y., Negishi, M., Irie, A., Ushikubi, F., Kakizuka, A., Ito, S., Ichikawa, A., and Narumiya, S. (1993) Alternative splicing of C-terminal tail of prostaglandin E receptor subtype EP3 determines G-protein specificity. Nature 365: 166–170.Google Scholar
  79. 79.
    Irie, A., Sugimoto, Y., Namba, T., Asano, T., Ichikawa, A., and Negishi, M. (1994) The C-terminus of the prostaglandin-E-receptor EP3 subtype is essential for activation of GTP-binding protein. Eur. J. Biochem. 224: 161–166.PubMedCrossRefGoogle Scholar
  80. 80.
    Pickering, D. S., Thomsen, C., Suzdak, P. D., Fletcher, E. J., Robitaille, R., Salter, M. W., MacDonald, J. F., Huang, X. P., and Hampson, D. R. (1993) A comparison of two alternatively spliced forms of a metabotropic glutamate receptor coupled to phosphoinositide turnover. J. Neurochem. 61: 85–92.PubMedCrossRefGoogle Scholar
  81. 81.
    Ohlstein, E. H., Nambi, P., and Ruffolo, R. R. (1995) Endothelin receptor subclassification, in Endothelin Receptors from the Gene to the Human ( Ruffolo, R. R., ed.), CRC, Boca Raton, FL, pp. 15–36.Google Scholar
  82. 82.
    Adachi, M., Furuichi, Y., and Miyamoto, C. (1994) Identification of a ligand-binding site of the human endothelin-A receptor and specific regions required for ligand selectivity. Eur. J. Biochem. 220: 37–43.PubMedCrossRefGoogle Scholar
  83. 83.
    Adachi, M., Furuichi, Y., and Miyamoto, C. (1994) Identification of specific regions of the human endothelin-B receptor required for high affinity binding with endothelin-3. Biochim. Biophys. Acta 1223: 202–208.PubMedCrossRefGoogle Scholar
  84. 84.
    Becker, A., Haendler, B., Hechler, U., and Schleuning, W. D. (1994) Mutational analysis of human endothelin receptors ETA and ETB identification of regions involved in the selectivity for endothelin 3 or cyclo(D-Trp-D-Asp-Pro-D-Val-Leu). Eur. J. Biochem. 221: 951–958.PubMedCrossRefGoogle Scholar
  85. 85.
    Lee, J. A., Elliott, J. D., Sutiphong, J. A., Friesen, W. J., Ohlstein, E. H., Stadel, J. M., Gleason, J. G., and Peishoff, C. E. (1994) Tyrosine 129 is important to the peptide ligand affinity and selectivity of human endothelin a receptor. Proc. Natl. Acad. Sci. USA 91: 7164–7168.PubMedCrossRefGoogle Scholar
  86. 86.
    Sakamoto, A., Yanagisawa, M., Sawamura, T., Enoki, T., Ohtani, T., Sakurai, T., Nakao, K., Toyo-oka, T., and Masaki, T. (1993) Distinct subdomains of human endothelin receptors determine their selectivity to endothelinA-selective antagonist and endothelinB-selective agonists. J. Biol. Chem. 268: 8547–8553.PubMedGoogle Scholar
  87. 87.
    Adachi, M., Yang, Y. Y., Trzeciak, A., Furuichi, Y., and Miyamoto, C. (1992) Identification of a domain of ETA receptor required for ligand binding. FEBS Letts. 311: 179–183.CrossRefGoogle Scholar
  88. 88.
    Hashido, K., Gamou, T., Adachi, M., Tabuchi, H., Watanabe, T., Furuichi, Y., and Miyamoto, C. (1992) Truncation of N-terminal extracellular or C-terminal intracellular domains of human ETA receptor abrogated the binding activity to ET-1. Biochem. Biophys. Res. Comm. 187: 1241–1248.PubMedCrossRefGoogle Scholar
  89. 89.
    Strader, C. D., Sigal, I. S., Register, R. B., Candelore, M. R., Rands, E., and Dixon, R. A. (1987) Identification of residues required for ligand binding to the beta-adrenergic receptor. Proc. Natl. Acad. Sci. USA 84: 4384–4388.PubMedCrossRefGoogle Scholar
  90. 90.
    Schwartz, T. W. (1994) Locating ligand-binding sites in 7TM receptors by protein engineering. Curr. Opin. Biotech. 5: 434–444.PubMedCrossRefGoogle Scholar
  91. 91.
    Surratt, C. K., Johnson, P. S., Moriwaki, A., Seidleck, B. K., Blaschak, C. J., Wang, J. B., and Uhl, G. R. (1994) Mu opiate receptor. Charged transmembrane domain amino acids are critical for agonist recognition and intrinsic activity. J. Biol. Chem. 269:20, 548–20, 553.Google Scholar
  92. 92.
    Perlman, J. H., Thaw, C. N., Laakkonen, L., Bowers, C. Y., Osman, R., and Gershengorn, M. C. (1994) Hydrogen bonding interaction of thyrotropin-releasing hormone (TRH) with transmembrane tyrosine 106 of the TRH receptor. J. Biol. Chem. 269: 1610–1613.PubMedGoogle Scholar
  93. 93.
    Ji, H., Leung, M., Zhang, Y., Catt, K. J., and Sandberg, K. (1994) Differential structural requirements for specific binding of nonpeptide and peptide antagonists to the AT1 angiotensin receptor. J. Biol. Chem. 268:16, 533–16, 536.Google Scholar
  94. 94.
    Hebert, C. A., Chuntharapai, A., Smith, M., Colby, T., Kim, J., and Horuk, R. (1993) Partial functional mapping of the human interleukin-8 type A receptor. Identification of a major ligand binding domain. J. Biol. Chem. 268:18, 549–18, 553.Google Scholar
  95. 95.
    Krystek, S. R., Jr., Patel, P. S., Rose, P. M., Fisher, S. M., Kienzle, B. K., Lach, D. A., Liu, E. C., Lynch, J. S., Novotny, J., and Webb, M. L. (1994) Mutation of peptide binding site in transmembrane region of a G protein-coupled receptor accounts for endothelin receptor subtype selectivity. J. Biol. Chem. 269, 12,383–12, 386.Google Scholar
  96. 96.
    Henderson, R., Baldwin, J. M., Ceska, T. A., Zemlin, F., Beckmann, E., and Downing, K. H. (1990) Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy. J. Mol. Biol. 213: 899–929.PubMedCrossRefGoogle Scholar
  97. 97.
    Zhu, G., Wu, L. H., Mauzy, C., Egloff, A. M., Mirzadegan, T., and Chung, F. Z. (1992) Replacement of lysine-181 by aspartic acid in the third trans-membrane region of endothelin type B receptor reduces its affinity to endothelin peptides and sarafotoxin 6c without affecting G protein coupling. J. Cell Biochem. 50: 159–164.PubMedGoogle Scholar
  98. 98.
    Mauzy, C., Wu, L. H., Egloff, A. M., Mirzadegan, T., and Chung, F. Z. (1992) Substitution of lysine-181 to aspartic acid in the third transmembrane region of the endothelin (ET) type B receptor selectively reduces its high-affinity binding with ET-3 peptide. J. Cardiovas. Pharmacol. 12: S5 — S7.CrossRefGoogle Scholar
  99. 99.
    Lee, J. A., Brinkmann, J. A., Longton, E. D., Peishoff, C. E., Lago, M. A., Leber, J. D., Cousins, R. D., Gao, A., Stadel, J. M., Kumar, C. S., Ohlstein, E. H., Gleason, J. G., and Elliott, J. D. (1994) Lysine 182 of endothelin b receptor modulates agonist selectivity and antagonist affinity: evidence for the overlap of peptide and non-peptide ligand binding sites. Biochemistry 33:14, 543–14, 549.Google Scholar
  100. 100.
    Han, M. and Smith, S. O. (1995) NMR Constraints on the location of the retinal chromophore in rhodopsin and bathorhodopsin. Biochemistry 34: 1425–1432.PubMedCrossRefGoogle Scholar
  101. 101.
    Elliott, J. D., Lago, M. A., and Peishoff, C. E. (1995) Endothelin receptor anatgonist, in Endothelin Receptors from the Gene to the Human ( Ruffolo, R. R., ed.), CRC, Boca Raton, FL, pp. 79–107.Google Scholar
  102. 102.
    Gether, U., Johansen, T. E., Snider, R. M., Lowe, J. A. D., Nakanishi, S., and Schwartz, T. W. (1993) Different binding epitopes on the NK1 receptor for substance P and non-peptide antagonist. Nature 362: 345–348.PubMedCrossRefGoogle Scholar
  103. 103.
    Gether, U., Yokota, Y., Emonds, A. X., Breliere, J. C., Lowe, J. A. d., Snider, R. M., Nakanishi, S., and Schwartz, T. W. (1993) Two nonpeptide tachykinin antagonists act through epitopes on corresponding segments of the NK1 and NK2 receptors. Proc. Natl. Acad. Sci. USA 90: 6194–6198.PubMedCrossRefGoogle Scholar
  104. 104.
    Fong, T. M., Cascieri, M. A., Yu, H., Bansal, A., Swain, C., and Strader, C. D. (1993) Amino-aromatic interaction between histidine 197 of the neurokinin-1 receptor and CP 96345. Nature 362: 350–353.PubMedCrossRefGoogle Scholar
  105. 105.
    Beinborn, M., Lee, Y. M., McBride, E. W., Quinn, S. M., and Kopin, A. S. (1993) A single amino acid of the cholecystokinin-B/gastrin receptor determines specificity for non-peptide antagonists. Nature 362: 348–350.PubMedCrossRefGoogle Scholar
  106. 106.
    Huang, R. R. C., Yu, H., Strader, C. D., and Fong, T. M. (1994) Interaction of substance P with the second and seventh transmembrane domains of the neurokinin-1 receptor. Biochemistry 33: 3007–3013.PubMedCrossRefGoogle Scholar
  107. 107.
    Schambye, H. T., Hjorth, S. A., Bergsma, D. J., Sathe, G., and Schwartz, T. W. (1994) Differentiation between binding sites for angiotensin II and nonpeptide antagonists on the angiotensin II type 1 receptors. Proc. Natl. Acad. Sci. USA 91: 7046–7050.PubMedCrossRefGoogle Scholar
  108. 108.
    Rosenkilde, M. M., Cahir, M., Gether, U., Hjorth, S. A., and Schwartz, T. W. (1994) Mutations along transmembrane segment II of the NK-1 receptor affect substance P competition with non-peptide antagonists but not substance P binding. J. Biol. Chem. 269:28, 160–28, 164.Google Scholar
  109. 109.
    Strader, C. D., Sigal, I. S., Candelore, M. R., Rands, E., Hill, W. S., and Dixon, R. A. (1988) Conserved aspartic acid residues 79 and 113 of the b-adrenergic receptor have different roles in receptor function. J. Biol. Chem. 263:10, 267–10, 271.Google Scholar
  110. 110.
    Wang, C. D., Buck, M. A., and Fraser, C. M. (1991) Site-directed mutagenesis of alpha 2A-adrenergic receptors: identification of amino acids involved in ligand binding and receptor activation by agonists. Mol. Pharm. 40: 168–179.Google Scholar
  111. 111.
    Wang, C. D., Gallaher, T. K., and Shih, J. C. (1993) Site-directed mutagenesis of the serotonin 5-hydroxytrypamine2 receptor: identification of amino acids necessary for ligand binding and receptor activation. Mol. Pharm. 43: 931–940.Google Scholar
  112. 112.
    Ho, B. Y., Karschin, A., Branchek, T., Davidson, N., and Lester, H. A. (1992) The role of conserved aspartate and serine residues in ligand binding and in function of the 5-HT1A receptor: a site-directed mutation study. FEBS Letts. 312: 259–262.CrossRefGoogle Scholar
  113. 113.
    Clackson, T. and Wells, J. A. (1995) A hot spot of binding energy in a hormone-receptor interface. Science 267: 383–386.PubMedCrossRefGoogle Scholar
  114. 114.
    Devereux, J., Haeberli, P., and Smithies, O. (1984) A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 12: 387–395.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Jonathan A. Lee
  • Eliot H. Ohlstein
  • Catherine E. Peishoff
  • John D. Elliott

There are no affiliations available

Personalised recommendations