Molecular Co-evolution of Gonadotropin-releasing Hormones and Their Receptors

  • Seong, Jae-Young (Grdauate School of Medicine, Korea University) ;
  • Kwon, Hyuk-Bang (Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University)
  • Published : 2007.12.31

Abstract

Gonadotropin-releasing hormone (GnRH), synthesized in the hypothalamus, plays a pivotal role in the regulation of vertebrate reproduction. Since molecular isoforms of GnRH and their receptors (GnRHR) have been isolated in a broad range of vertebrate species, GnRH and GnRHR provide an excellent model for understanding the molecular co-evolution of a peptide ligand-receptor pair. Vertebrate species possess multiple forms of GnRH, which have been created through evolutionary mechanisms such as gene/chromosome duplication, gene deletion and modification. Similar to GnRHs, GnRH receptors (GnRHR) have also been diversified evolutionarily. Comparative ligand-receptor interaction studies for non-mammalian and mammalian GnRHRs combined with mutational mapping studies of GnRHRs have aided the identification of domains or motifs responsible for ligand binding and receptor activation. Here we discuss the molecular basis of GnRH-GnRHR co-evolution, particularly the structure-function relationship regarding ligand selectivity and signal transduction of mammalian and non-mammalian GnRHRs.

References

  1. Arora KK, Krsmanovic LZ, Mores N, O'Farrell H and Catt KJ (1998) Mediation of cyclic AMP signaling by the first intracellular loop of the gonadotropin-releasing hormone receptor. J Biol Chem 273: 25581-25586 https://doi.org/10.1074/jbc.273.40.25581
  2. Azad N, Emanuele NV, Halloran MM, Tlentler J and Kelley MR (1991) Presence of luteinizing hormone-releasing hormone (LHRH) mRNA in rat spleen lymphocytes. Endocrinology 128: 1679-1681 https://doi.org/10.1210/endo-128-3-1679
  3. Bogerd J, Diepenbroek WB, Hund E, van Oosterhout F, Teves AC, Leurs R and Blomenrohr M (2002) Two gonadotropin-releasing hormone receptors in the African catfish: no differences in ligand selectivity, but differences in tissue distribution. Endocrinology 143: 4673-4682 https://doi.org/10.1210/en.2002-220578
  4. Chen A, Ganor Y, Rahimipour S, Ben-Aroya N, Koch Y and Levite M (2002b) The neuropeptides GnRH-II and GnRH-I are produced by human T cells and trigger laminin receptor gene expression, adhesion, chemotaxis and homing to specific organs. Nat Med 8: 1421-1426 https://doi.org/10.1038/nm801
  5. Chen A, Kaganovsky E, Rahimipour S, Ben-Aroya N, Okon E and Koch Y (2002a) Two forms of gonadotropin-releasing hormone (GnRH) are expressed in human breast tissue and overexpressed in breast cancer: a putative mechanism for the antiproliferative effect of GnRH by down-regulation of acidic ribosomal phosphoproteins P1 and P2. Cancer Res 62: 1036-1044
  6. Davidson JS, McArdle CA, Davies P, Elario R, Flanagan CA and Millar RP (1996) Asn102 of the gonadotropin-releasing hormone receptor is a critical determinant of potency for agonists containing C-terminal glycinamide. J Biol Chem 271: 15510-15514 https://doi.org/10.1074/jbc.271.26.15510
  7. Densmore VS and Urbanski HF (2003) Relative effect of gonadotropin-releasing hormone (GnRH)-I and GnRH-II on gonadotropin release. J Clin Endocrinol Metab 88: 2126-2134 https://doi.org/10.1210/jc.2002-021359
  8. Faurholm B, Millar RP and Katz AA (2001) The genes encoding the type II gonadotropin-releasing hormone receptor and the ribonucleoprotein RBM8A in humans overlap in two genornic loci. Genomics 78: 15-18 https://doi.org/10.1006/geno.2001.6650
  9. Fernald RD and White RB (1999) Gonadotropin-releasing hormone genes: phylogeny, structure, and functions. Front Neuroendocrinol 20: 224-240 https://doi.org/10.1006/frne.1999.0181
  10. Flanagan CA, Becker, II, Davidson JS, Wakefield IK, Zhou W, Sealfon SC and Millar RP (1994) Glutamate 301 of the mouse gonadotropin-releasing hormone receptor confers specificity for arginine 8 of mammalian gonadotropin-releasing hormone. J Biol Chem 269: 22636-22641
  11. Flanagan CA, Rodic V, Konvicka K, Yuen T, Chi L, Rivier JE, Millar RP, Weinstein Hand Sealfon SC (2000) Multiple interactions of the Asp(2.61(98)) side chain of the gonadotropin-releasing hormone receptor contribute differentially to ligand interaction. Biochemistry 39: 8133-8141 https://doi.org/10.1021/bi000085g
  12. Flanagan CA, Zhou W, Chi L, Yuen T, Rodic V, Robertson D, Johnson M, Holland P, Millar RP, Weinstein H, Mitchell R and Sealfon SC (1999) The functional microdomain in transmembrane helices 2 and 7 regulates expression, activation, and coupling pathways of the gonadotropin-releasing hormone receptor. J Biol Chem 274: 28880-28886 https://doi.org/10.1074/jbc.274.41.28880
  13. Gault PM, Morgan K, Pawson AJ, Millar RP and Lincoln GA (2004) Sheep exhibit novel variations in the organization of the mammalian type II gonadotropin-releasing hormone receptor gene. Endocrinology 145: 2362-2374 https://doi.org/10.1210/en.2003-1625
  14. Grosse R, Schmid A, Schoneberg T, Herrlich A, Muhn P, Schultz G and Gudermann T (2000) Gonadotropin-releasing hormone receptor initiates multiple signaling pathways by exclusively coupling to G(q/11) proteins. J Biol Chem 275: 9193-9200 https://doi.org/10.1074/jbc.275.13.9193
  15. Grundker C, Schlotawa L, Viereck V, Eicke N, Horst A, Kairies B and Emons G (2004) Antiproliferative effects of the GnRH antagonist cetrorelix and of GnRH-II on human endometrial and ovarian cancer cells are not mediated through the GnRH type I receptor. Eur J Endocrinol 151: 141-149 https://doi.org/10.1530/eje.0.1510141
  16. Heding A, Vrecl M, Bogerd J, McGregor A, Sellar R, Taylor PL and Eidne KA (1998) Gonadotropin-releasing hormone receptors with intracellular carboxyl-terminal tails undergo acute desensitization of total inositol phosphate production and exhibit accelerated internalization kinetics. J Biol Chem 273: 11472-11477 https://doi.org/10.1074/jbc.273.19.11472
  17. Hovelmann S, Hoffmann SH, Kuhne R, ter Laak T, Reilander H and Beckers T (2002) Impact of aromatic residues within transmembrane helix 6 of the human gonadotropin-releasing hormone receptor upon agonist and antagonist binding. Biochemistry 41: 1129-1136 https://doi.org/10.1021/bi0113162
  18. llling N, Troskie BE, Nahorniak CS, Hapgood lP, Peter RE and Millar RP (1999) Two gonadotropin-releasing hormone receptor subtypes with distinct ligand selectivity and differential distribution in brain and pituitary in the goldfish (Carassius auratus). Proc Natl Acad Sci USA 96: 2526-2531
  19. Kah O, Lethimonier C, Somoza G; Guilgur LG, Vaillant C and Lareyre JJ (2007) GnRH and GnRH receptors in metazoa: a historical, comparative, and evolutive perspective. Gen Comp Endocrinol 153: 346-364 https://doi.org/10.1016/j.ygcen.2007.01.030
  20. Li JH, Choe H, Wang AF, Maiti K, Wang C, Salam A, Chun SY, Lee WK, Kim K, Kwon HB and Seong JY (2005) Extracellular loop 3 (EL3) and EL3-proximal transmembrane helix 7 of the mammalian type I and type II gonadotropinreleasing hormone (GnRH) receptors determine differential ligand selectivity to GnRH-l and GnRH-II. Mol Pharmacol 67: 1099-1110 https://doi.org/10.1124/mol.104.004887
  21. Maiti K, Li JH, Wang AF, Acharjee S, Kim WP, Im WB, Kwon HB and Seong JY (2003) GnRH-II analogs for selective activation and inhibition of non-mammalian and type-II mammalian GnRH receptors. Mol Cells 16: 173-179
  22. Maiti K, Oh DY, Moon JS, Acharjee S, Li JH, Bai DG, Park HS, Lee K, Lee YC, Jung NC, Kim K. Vaudry H, Kwon HB and Seong JY (2005) Differential effects of gonadotropin-releasing hormone (GnRH)-I and GnRH-Il on prostate cancer cell signaling and death. J Clin Endocrinol Metab 90: 4287-4298 https://doi.org/10.1210/jc.2004-1894
  23. Mason AJ, Hayflick JS, Zoeller RT, Young WS, 3rd, Phillips HS, Nikolics K and Seeburg PH (1986) A deletion truncating the gonadotropin-releasing hormone gene is responsible for hypogonadism in the hpg mouse. Science 234: 1366-1371 https://doi.org/10.1126/science.3024317
  24. Matsuo H, Baba Y, Nair RM, Arirnura A and Schally AV (1971) Structure of the porcine LH- and FSH-releasing hormone. I. The proposed amino acid sequence. Biochem Biophys Res Commun 43: 1334-1339 https://doi.org/10.1016/S0006-291X(71)80019-0
  25. Millar R, Lowe S, Conklin D, Pawson A, Maudsley S, Troskie B, Ott T, Millar M, Lincoln G, Sellar R, Faurholm B, Scobie G, Kuestner R, Terasawa E and Katz A (2001) A novel mammalian receptor for the evolutionarily conserved type II GnRH. Proc Natl Acad Sci USA 98: 9636-9641
  26. Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K and Maudsley SR (2004) Gonadotropin-releasing hormone receptors. Endocr Rev 25: 235-275 https://doi.org/10.1210/er.2003-0002
  27. Moncaut N, Somoza G, Power DM and Canario AV (2005) Five gonadotrophin-releasing hormone receptors in a teleost fish: isolation, tissue distribution and phylogenetic relationships. J Mol Endocrinol 34: 767-779 https://doi.org/10.1677/jme.1.01757
  28. Morgan K, Conklin D, Pawson AJ, Sellar R, Ott TR and Millar RP (2003) A transcriptionally active human type II gonadotropin-releasing hormone receptor gene homolog overlaps two genes in the antisense orientation on chromosome 1q.12. Endocrinology 144: 423-436 https://doi.org/10.1210/en.2002-220622
  29. Oh DY, Song JA, Moon JS, Moon MJ, Kim JI, Kim K, Kwon HB and Seong JY (2005) Membrane-proximal region of the carboxyl terminus of the gonadotropin-releasing hormone receptor (GnRHR) confers differential signal transduction between mammalian and nonmammalian GnRHRs. Mol Endocrinol 19: 722-731 https://doi.org/10.1210/me.2004-0220
  30. Oh DY, Wang L, Ahn RS, Park JY, Seong JY and Kwon HB (2003) Differential G protein coupling preference of mammalian and nonmammalian gonadotropin-releasing hormone receptors. Mol Cell Endocrinol 205: 89-98 https://doi.org/10.1016/S0303-7207(03)00204-1
  31. Oikawa M, Dargan C, Ny T and Hsueh AJ (1990) Expression of gonadotropin-releasing hormone and prothymosin-alpha messenger ribonucleic acid in the ovary. Endocrinology 127: 2350-2356 https://doi.org/10.1210/endo-127-5-2350
  32. Okada Y, Murota-Kawano A, Kakar SS and Winters Sl (2003) Evidence that gonadotropin-releasing hormone (GnRH) II stimulates luteinizing hormone and follicle-stimulating hormone secretion from monkey pituitary cultures by activating the GnRH I receptor. Biol Reprod 69: 1356-1361 https://doi.org/10.1095/biolreprod.103.016162
  33. Powell JF, Zohar Y, Elizur A, Park M, Fischer WH, Craig AG, Rivier JE, Lovejoy DA and Sherwood NM (1994) Three forms of gonadotropin-releasing hormone characterized from brains of one species. Proc Natl Acad Sci USA 91: 12081-12085
  34. Seong JY, Wang L, Oh da Y, Yun O, Maiti K, Li JR, Soh JM, Choi HS, Kim K, Vaudry H and Kwon HB (2003) Ala/Thr(201) in extracellular loop 2 and Leu/Phe(290) in transmembrane domain 6 of type 1 frog gonadotropin-releasing hormone receptor confer differential ligand sensitivity and signal transduction. Endocrinology 144: 454-466 https://doi.org/10.1210/en.2002-220683
  35. Troskie B, King JA, Millar RP, Peng YY, Kim J, Figueras Hand Illing N (1997) Chicken GnRH Il-like peptides and a GnRH receptor selective for chicken GnRH II in amphibian sympathetic ganglia. Neuroendocrinology 65: 396-402 https://doi.org/10.1159/000127202
  36. Troskie BE, Hapgood JP, Millar RP and Illing N (2000) Complementary deoxyribonucleic acid cloning, gene expression, and ligand selectivity of a novel gonadotropinreleasing hormone receptor expressed in the pituitary and midbrain of Xenopus laevis. Endocrinology 141: 1764-1771 https://doi.org/10.1210/en.141.5.1764
  37. Tsutsumi M, Zhou W, Millar RP, Mellon PL, Roberts JL, Flanagan CA, Dong K, Gillo B and Sealfon SC (1992) Cloning and functional expression of a mouse gonadotropin-releasing hormone receptor. Mol Endocrinol 6: 1163-1169 https://doi.org/10.1210/me.6.7.1163
  38. Urbanski HF, White RB, Fernald RD, Kohama So, Garyfallou VT and Densmore VS (1999) Regional expression of mRNA encoding a second form of gonadotropin-releasing hormone in the macaque brain. Endocrinology 140: 1945-1948 https://doi.org/10.1210/en.140.4.1945
  39. Wang AF, Li JH, Maiti K, Kim WP, Kang HM, Seong JY and Kwon HB (2003) Preferential ligand selectivity of the monkey type-II gonadotropin-releasing hormone (GnRH) receptor for GnRH-2 and its analogs. Mol Cell Endocrinol 209: 33-42 https://doi.org/10.1016/j.mce.2003.08.004
  40. Wang C, Yun O, Maiti K, Oh DY, Kim KK, Chae CH, Lee CJ, Seong JY and Kwon HB (2004) Position of Pro and Ser near Glu7.32 in the extracellular loop 3 of mammalian and nonmammalian gonadotropin-releasing hormone (GnRH) receptors is a critical determinant for differential ligand selectivity for mammalian GnRH and chicken GnRH-II. Mol Endocrinol 18: 105-116 https://doi.org/10.1210/me.2003-0101
  41. Wang L, Bogerd J, Choi HS, Seong JY, Soh JM, Chun SY, Blomenrohr M, Troskie BE, Millar RP, Yu WH, McCann SM and K won HB (2001) Three distinct types of GnRH receptor characterized in the bullfrog. Proc Natl Acad Sci USA 98: 361-366
  42. White RB, Eisen JA, Kasten TL and Fernald RD (1998) Second gene for gonadotropin-releasing hormone in humans. Proc Natl Acad Sci USA 95: 305-309
  43. Yoo MS, Kang HM, Choi HS, Kim JW, Troskie BE, Millar RP and Kwon HB (2000) Molecular cloning, distribution and pharmacological characterization of a novel gonadotropin-releasing hormone ([Trp8] GnRH) in frog brain. Mol Cell Endocrinol 164: 197-204 https://doi.org/10.1016/S0303-7207(00)00221-5