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The Structure-Activity Relationships of the Luteinizing Hormone Receptor

  • Brian A. Cooke
  • Anthony P. West
Conference paper
Part of the Schering Foundation Workshop book series (SCHERING FOUND, volume 4)

Abstract

LH (luteinizing hormone, lutropin) and its homologue chorionic gonadotropin (CG) play a central role in the control of ovulation, pregnancy and testicular function. They belong to a family of polypeptide trophic hormones which also includes follicle stimulating hormone (FSH) and thyroid stimulating hormone (TSH). An important aspect of the control of their target organs is the dynamic trafficking of their receptors, which, after hormone-induced activation of their transducing systems, may be followed by uncoupling, internalization and recycling and/or downregulation and new synthesis. This trafficking is especially im-
Fig. 1

The trafficking of the LH receptor. LH binds to the extracellular domain of the LHR which presumably causes a conformational change so that activation of the G protein, which in turn activates the adenylate cyclase, can take place. The receptor is thought to be continuously internalized, degraded and/or recycled. Alternatively, the extracellular fragment is cleaved by proteases and released into the extracellular medium

portant for the LH receptor (LHR), which in the Leydig cell of the testis is a continuous process (Fig. 1), whereas in the ovary it is dependent on the stage of the cycle. Very little is known about the mechanisms involved. However, with the recent elucidation of the sequences and structures of these receptors (Loosfelt et al. 1989; McFarland et al. 1989; Minegishi et al.1990; Misrahi et al.1990; Jia et al.1991; Sprengel et al.1990) the mechanisms can now be elucidated. It is the purpose of this short review to highlight the mechanisms and species differences of desensitization and downregulation of the testis Leydig cell LHR. We will describe an adaptation of the antisense oligodeoxynucleotide strategy which we have used to investigate the roles of the C-terminal sequences of the LHR in these processes.

Keywords

Luteinizing Hormone Thyroid Stimulate Honnone Leydig Cell Luteinizing Hormone Receptor Thyroid Stimulate Honnone Receptor 
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.

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References

  1. Catt KJ, Harwood JP, Aguilera G, Dufau ML (1979) Hormonal regulation of peptide receptors and target cell responses. Nature 280: 109–116PubMedCrossRefGoogle Scholar
  2. Cooke BA (1990) Is cyclic AMP an obligatory second messenger for luteinizing hormone? Mol Cell Endocrinol 69: C11 - C15PubMedCrossRefGoogle Scholar
  3. Cooke BA, Rommerts FFG (1988) The mechanisms of action of luteinizing hormone I. Luteinizing hormone-receptor interactions. In: Cooke BA, King RJB, van der Molen HJ, (eds) New comprehensive biochemistry: Hormones and their actions, Vol II. Elsevier, Amsterdam, pp 155–162Google Scholar
  4. Heikkila R, Schwab G, Wickstrom E, Loke SL, Lpuznik DH, Watt R, Neckers LM (1987) A c-myc antisense oligodeoxymucleotide inhibits entry into S phase but not progress from Go to Gi. Nature 328: 445–449PubMedCrossRefGoogle Scholar
  5. Hu ZZ, Tsaimorris CH, Buczko E, Dufau ML (1990) Hormonal regulation of LH receptor messenger RNA and expression in the rat ovary. FEBS Lett 274: 181–184PubMedCrossRefGoogle Scholar
  6. Jaskulski D, Kim deRiel J, Calabretta B, Baserga R (1988) Inhibition of cellular proliferation by antisense oligodeoxynucleotides to PCNA cyclin. Science 240: 1544–1546PubMedCrossRefGoogle Scholar
  7. Ji I, Ji TH (1991) Exons 1–10 of the rat LH receptor encode a high affinity hormone binding site and exon 11 encodes G-protein modulation and a potential second hormone binding site. Endocrinology 128: 2648–2650PubMedCrossRefGoogle Scholar
  8. Jia XC, Oikawa M, Bo M, Tanaka T, Ny T, Boime I, Hsueh AJW (1991) Expression of human luteinizing hormone ( LH) receptor - interaction with LH and chorionic gonadotropin from human but not equine, rat, and ovine species. Mol Endocrinol 5: 759–768PubMedCrossRefGoogle Scholar
  9. Lapolt PS, Jia XC, Sincich C, Hsueh AJW (1991) Ligand-induced down-regulation of testicular and ovarian luteinizing hormone ( LH) receptors is preceeded by tissue-specific inhibition of alternatively processed LH receptor transcripts. Mol Endocrinol 5: 397–403PubMedCrossRefGoogle Scholar
  10. Lawrence JC, Hiken W, James DE (1990) Phosphorylation of the glucose transporter in rat adipocytes. Identification of the intracellular domain at the carboxyl terminus as a target for phosphorylation in intact-cells and in vitro. J biol Chem 265: 2324–2332PubMedGoogle Scholar
  11. Lohse MJ, Lefkowitz RJ, Caron MG, Benovic JL (1989) Inhibition of ßadrenergic receptor kinase prevents rapid homologous desensitization of ß2-adrenergic receptors. Proc Natl Acad Sci 86: 3011–3015PubMedCrossRefGoogle Scholar
  12. Loosfelt H, Misrahi M, Atger M, Salesse R, Thi MTVH-L, Jolivet A, Guiochon-Mantel A, Sar S, Jallal B, Gamier J, Milgrom E (1989) Cloning and sequencing of porcine LH-hCG receptor cDNA; variants lacking trans-membrane domain. Science 245: 525–528PubMedCrossRefGoogle Scholar
  13. McFarland KC, Sprengel R, Phillips HS, Kohler M, Rosemblit N, Nikolics K, Segaloff DL, Seeberg PH (1989) Lutropin-choriogonadotropin receptor; an unusual member of the G protein coupled receptor family. Science 245: 494–499PubMedCrossRefGoogle Scholar
  14. Minegishi T, Delgado C, Dufau ML (1989) Phosphorylation and glycosylation of the luteinizing hormone receptor. Proc Natl Acad Sci 86: 1470–1474PubMedCrossRefGoogle Scholar
  15. Minegishi T, Nakamura K, Takakura Y, Miyamota K, Hasegawa Y, Ibuki Y, Igarashi M (1990) Cloning and sequencing of human LH/hCG receptor cDNA. Biochem biophys Res Comm 172: 1049–1054PubMedCrossRefGoogle Scholar
  16. Misrahi M, Loosfelt H, Atger M, Sar S, Guiochonmantel A, Milgrom E (1990) Cloning, sequencing and expression of human TSH receptor. Bioc Biop R 166: 394–403CrossRefGoogle Scholar
  17. Palm D, Munch G, Dees C, Hekman M (1990) Identification of a Gs-protein coupling domain to the ß-aderenoceptor using site-specific synthetic peptides. Carboxyl terminus of Gs is involved in coupling to (3-adenoceptors. FEBS Letter 261: 294–298CrossRefGoogle Scholar
  18. Rebois RV, Fishman PH (1984) Down regulation of gonadotropin receptors in a murine Leydig tumour cell line. J biol Chem 259: 3096–3101PubMedGoogle Scholar
  19. Rommerts FFG, Cooke BA (1988) The mechanisms of action of luteinizing hormone. II. Transducing systems and biological effects. In: Cooke BA, King RJB, van der Molen HJ (eds) New comprehensive biochemistry: Hormones and their actions, Vol II. Elsevier, Amsterdam, pp 163–180Google Scholar
  20. Segaloff DL, Sprengel R, Nikolics K, Ascoli M (1990) Structure of the lu- tropin/choriogonadotropin receptor. Rec Prog Horm Res 46: 261–301PubMedGoogle Scholar
  21. Sprengel R, Braun T, Nikobis K, Segaloff DL, Seeburg PH (1990) The testicular receptor for follicle stimulating hormone: structure and functional expression of cloned cDNA. Mol Endocrinol 4: 525–530PubMedCrossRefGoogle Scholar
  22. Taylor CW (1990) The role of G proteins in transmembrane signalling. Biochem J 272: 1–13PubMedGoogle Scholar
  23. Tortora G, Clair T, Cho-Chung YS (1990) An antisense oligodeoxynucleotide targeted against the type 1I13 regulatory subtype mRNA of protein kinase inhibits cAMP-induced differentiation in HL-60 leukemia cells without affecting phorbol ester effects. Proc Natl Acad Sci 87: 705–708PubMedCrossRefGoogle Scholar
  24. Tsai-Morris CH, Buczko E, Wang W, Dufau ML (1990) Intronic nature of the rat luteinizing receptor gene defines a soluble receptor subspecies with hormone binding activity. J biol Chem 265: 19385–19388PubMedGoogle Scholar
  25. Wang H, Segaloff DL, Ascoli M (1991) Lutropin/choriogonadotropin down-regulates its receptor by both receptor-mediated endocytosis and a cAMPdependent reduction in receptor mRNA. J biol Chem 266: 780–785PubMedGoogle Scholar
  26. West AP, Rose MP, Cooke BA (1990) Induction of lutropin receptors by lutropin and 3’5’-cyclic AMP in cultured mouse tumour (MA10) Leydig cells. Biochem J 270: 499–503PubMedGoogle Scholar
  27. West AP, Lopez-Ruiz MP, Cooke BA (1991a) Differences in LH receptor down regulation between rat and mouse Leydig cells: Effects of 3’,5’-cyclic AMP and phorbol esters. Mol Cell Endocrinol 77: R7 - R11PubMedCrossRefGoogle Scholar
  28. West AP, Phipp LH, Cooke BA (1991b) Evidence for the requirement of proteolysis in LH stimulated cyclic AMP production and steroidogenesis in Leydig cells. FEBS Letter 282: 239–241CrossRefGoogle Scholar
  29. West AP, Cooke BA (1991a) Regulation of the truncation of luteinizing hormone receptors at the plasma membrane is different in rat and mouse Leydig cells. Endocrinology 128: 363–370PubMedCrossRefGoogle Scholar
  30. West AP, Cooke BA (199 lb) A novel method to modulate desensitization and truncation of LH receptors using antisense oliodeoxynucleotides. Mol Cell Endocrinol 79: R9 - R14Google Scholar
  31. Xie Y-B, Wang H, Segaloff DL (1990) Extracellular domain of lutropin/choriogonadotropin receptor espressed in transfected cells binds choriogonadotropin with high affinity. J Biol Chem 265: 21411–21414PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1992

Authors and Affiliations

  • Brian A. Cooke
  • Anthony P. West

There are no affiliations available

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