Relaxin family peptide receptors - Former orphans reunite with their parent ligands to activate multiple signalling pathways

British Journal of Pharmacology

Volumn 150, Issue 6, 2007, Pages 677-691

  Halls, M L ^a   Van Der Westhuizen, E T ^a   Bathgate, R A D ^b   Summers, R J ^a  

^a MONASH UNIVERSITY   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

H1 relaxin; H2 relaxin; H3 relaxin; INSL3; INSL5; RXFP1 (LGR7); RXFP2 (LGR8); RXFP3 (GPCR135, SALPR); RXFP4 (GPCR142, GPR100)

Indexed keywords

ADENYLATE CYCLASE; CYCLIC AMP; LEUCINE; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; RECEPTOR; RECEPTOR SUBUNIT; RELAXIN; RELAXIN 3; RELAXIN FAMILY PEPTIDE RECEPTOR; RELAXIN FAMILY PEPTIDE RECEPTOR 1; RELAXIN FAMILY PEPTIDE RECEPTOR 2; RELAXIN FAMILY PEPTIDE RECEPTOR 3; RELAXIN FAMILY PEPTIDE RECEPTOR 4; UNCLASSIFIED DRUG;

AMINO TERMINAL SEQUENCE; BINDING AFFINITY; BINDING SITE; CARBOXY TERMINAL SEQUENCE; DNA SPLICING; ENZYME ACTIVATION; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; GENETIC ANALYSIS; GENETIC VARIABILITY; HUMAN; INHIBITION KINETICS; MEMBRANE POTENTIAL; MOLECULAR EVOLUTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN STRUCTURE; RECEPTOR BINDING; REVIEW; SEQUENCE ANALYSIS; SIGNAL TRANSDUCTION;

AMINO ACID SEQUENCE; ANIMALS; CONSERVED SEQUENCE; EVOLUTION, MOLECULAR; FEMALE; HUMANS; LIGANDS; MALE; MODELS, BIOLOGICAL; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; PROTEIN ISOFORMS; RECEPTORS, G-PROTEIN-COUPLED; RECEPTORS, PEPTIDE; RELAXIN; SEQUENCE HOMOLOGY, AMINO ACID; SIGNAL TRANSDUCTION; TISSUE DISTRIBUTION;

EID: 33947324489     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1038/sj.bjp.0707140     Document Type: Review

References (86)

1. Ascoli M, Fanelli F, Segaloff DL (2002). The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev 23: 141-174.
2. Bartsch O, Bartlick B, Ivell R (2001). Relaxin signalling links tyrosine phosphorylation to phosphodiesterase and adenylyl cyclase activity. Mol Human Reprod 7: 799-809.
3. Bartsch O, Bartlick B, Ivell R (2004). Phosphodiesterase 4 inhibition synergizes with relaxin signaling to promote decidualization of human endometrial stromal cells. J Clin Endocrinol Metab 89: 324-334.
4. Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ (2006a). International Union of Pharmacology LVII: recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev 58: 7-31.
5. Bathgate RA, Lin F, Hanson NF, Otvos Jr L, Guidolin A, Giannakis C et al. (2006b). Relaxin-3: improved synthesis strategy and demonstration of its high-affinity interaction with the relaxin receptor LGR7 both in vitro and in vivo. Biochemistry 45: 1043-1053.
6. Bathgate RA, Samuel CS, Burazin TC, Gundlach AL, Tregear, GW (2003). Relaxin: new peptides, receptors and novel actions. Trends Endocrin Metab 14: 207-213.
7. Bathgate, RAD, Hsueh, AJW, Sherwood OD (2006c). Physiology and molecular biology of the relaxin peptide family. In: Neill JD (ed) Knobil and Neill's Physiology of Reproduction 3rd edn. Academic Press, New York.
8. Bespalova IN, Angelo GW, Durner M, Smith CJ, Siever LJ, Buxbaum JD et al. (2005). Fine mapping of the 5p13 locus linked to schizophrenia and schizotypal personality disorder in a Puerto Rican family. Psychiatr Genet 15: 205-210.
9. Boels K, Schaller HC (2003). Identification and characterisation of GPR100 as a novel human G-protein-coupled bradykinin receptor. Br J Pharmacol 140: 932-938.
10. Bogatcheva NV, Truong A, Feng S, Engel W, Adham IM, Agoulnik AI (2003). GREAT/LGR8 is the only receptor for insulin-like 3 peptide. Mol Endocrinol 17: 2639-2646.
11. Bouhouche A, Benomar A, Birouk N, Mularoni A, Meggouh F, Tassin J et al. (1999). A locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 1q21.2-q21.3. Am J Hum Genet 65: 722-727.
12. Braddon SA (1978). Relaxin-dependent adenosine 6′,5′- monophosphate concentration changes in the mouse pubic symphysis. Endocrinology 102: 1292-1299.
13. Bullesbach EE, Schwabe C (2005a). LGR8 signal activation by the relaxin-like factor. J Biol Chem 280: 14856-14890.
14. Bullesbach EE, Schwabe C (2005b). The trap-like relaxin-binding site of LGR7. J Biol Chem 280: 14051-14056.
15. Bullesbach EE, Schwabe C (2006). The mode of interaction of the relaxin-like factor (RLF) with the leucine-rich repeat G protein-activated receptor 8. J Biol Chem 281: 26136-26143.
16. Burazin TC, Bathgate RA, Macris M, Layfield S, Gundlach AL, Tregear GW (2002). Restricted, but abundant, expression of the novel rat gene-3 (R3) relaxin in the dorsal tegmental region of brain. J Neurochem 82: 1553-1557.
17. Cheah SH, Sherwood OD (1980). Target tissues for relaxin in the rat: tissue distribution of injected 125I-labeled relaxin and tissue changes in adenosine 3′,5′-monophosphate levels after in vitro relaxin incubation. Endocrinology 106: 1203-1209.
18. Chen J, Kuei C, Sutton SW, Bonaventure P, Nepomuceno D, Eriste E et al. (2005). Pharmacological characterization of relaxin-3/INSL7 receptors GPCR135 and GPCR142 from different mammalian species. J Pharmacol Exp Ther 312: 83-95.
19. Conrad KP, Novak J (2004). Emerging role of relaxin in renal and cardiovascular function. Am J Physiol Regul Integr Comp Physiol 287: R250-R261.
20. Del Borgo MP, Hughes RA, Bathgate RA, Lin F, Kawamura K, Wade JD (2006). Analogs of insulin-like peptide 3 (INSL3) B-chain are LGR8 antagonists in vitro and in vivo. J Biol Chem 281: 13068-13074.
21. Dschietzig T, Bartsch C, Stangl V, Baumann G, Stangl K (2004). Identification of the pregnancy hormone relaxin as glucocorticoid receptor agonist. FASEB J 18: 1536-1538.
22. Du XJ, Samuel CS, Gao XM, Zhao L, Parry LJ, Tregear GW (2003). Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype. Cardiovasc Res 57: 395-404.
23. Feng S, Bogatcheva NV, Kamat AA, Truong A, Agoulnik AI (2006). Endocrine effects of relaxin overexpression in mice. Endocrinology 147: 407-414.
24. Gorlov IP, Kamat A, Bogatcheva NV, Jones E, Lamb DJ, Truong A et al. (2002). Mutations of the GREAT gene cause cryptorchidism. Hum Mol Genet 11: 2309-2318.
25. Graves PN, Tomer Y, Davies TF (1992). Cloning and sequencing of a 1.3 KB variant of human thyrotropin receptor mRNA lacking the transmembrane domain. Biochem Biophys Res Commun 187: 1135-1143.
26. Halls ML, Bathgate RA, Summers RJ (2006). Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP signaling by distinct mechanisms. Mol Pharmacol 70: 214-226.
27. Halls ML, Bond CP, Sudo S, Kumagai J, Ferraro T, Layfield S et al. (2005). Multiple binding sites revealed by interaction of relaxin family peptides with native and chimeric relaxin family peptide receptors 1 and 2 (LGR7 and LGR8). J Pharmacol Exp Ther 313: 677-687.
28. Heuser JE, Anderson RG (1989). Hypertonic media inhibit receptor-mediated endocytosis by blocking clathrin-coated pit formation. J Cell Biol 108: 389-400.
29. Hida T, Takahashi E, Shikata K, Hirohashi T, Sawai T, Seiki T et al. (2006). Chronic intracerebroventricular administration of relaxin-3 increases body weight in rats. J Recept Signal Transduct Res 26: 147-158.
30. Hisaw FL (1926). Experimental relaxation of the pubic ligament of the guinea pig. Proc Soc Exp Biol Med 23: 661-663.
31. Hombach-Klonisch S, Hoang-Vu C, Kehlen A, Hinze R, Holzhausen HJ, Weber E et al. (2003). INSL-3 is expressed in human hyperplastic and neoplastic thyrocytes. Int J Oncol 22: 993-1001.
32. Hsu SY (2003). New insights into the evolution of the relaxin-LGR signaling system. Trends Endocrin Met 14: 303-309.
33. Hsu SY, Kudo M, Chen T, Nakbayashi K, Bhalla A, Van Der Spek PJ et al. (2000). The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol Endocrinol 14: 1257-1271.
34. Hsu SY, Liang SG, Hsueh AJ (1998). Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol Endocrinol 12: 1830-1845.
35. Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD et al. (2002a). Activation of orphan receptors by the hormone relaxin. Science 25: 637-638.
36. Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD et al. (2002b). Activation of orphan receptors by the hormone relaxin [comment]. Science 25: 671-674.
37. Hsu SY, Semyonov J, Park JI, Chang CL (2005). Evolution of the signaling system in relaxin-family peptides. Ann NY Acad Sci 1041: 520-529.
38. Ivell R, Bathgate R (2006). Neohormone systems as exciting targets for drug development. Trends Endocrin Met 17: 123.
39. Judson DG, Pay S, Bhoola KD (1980). Modulation of cyclic AMP in isolated rat uterine tissue slices by porcine relaxin. J Endocrinol 87: 153-159.
40. Kamat AA, Feng S, Bogatcheva NV, Truong A, Bishop CE, Agoulnik AI (2004). Genetic targeting of relaxin and insulin-like factor 3 receptors in mice. Endocrinology 145: 4712-4720.
41. Kawamura K, Kumagai J, Sudo S, Chun SY, Pisarska M, Morita H et al. (2004). Paracrine regulation of mammalian oocyte maturation and male germ cell survival. Proc Natl Acad Sci USA 101: 7323-7328.
42. Kobe B, Deisenhofer J (1993). Crystal structure of porcine ribonuclease inhibitor, a protein with leucine-rich repeats. Nature 366: 751-756.
43. Kobe B, Kajava AV (2001). The leucine-rich repeat as a protein recognition motif. Curr Opin Struct Biol 11: 725-732.
44. Kohsaka T, Min G, Lukas G, Trupin S, Campbell ET, Sherwood OD (1998). Identification of specific relaxin-binding cells in the human female. Biol Reprod 59: 991-999.
45. Kraaij R, Verhoef-Post M, Grootegoed JA, Themmen AP (1998). Alternative splicing of follicle-stimulating hormone receptor pre-mRNA: cloning and characterization of two alternatively spliced mRNA transcripts. J Endocrinol 158: 127-136.
46. Krajnc-Franken MA, Van Disseldorp AJ, Koenders JE, Mosselman S, Van Duin M, Gossen JA (2004). Impaired nipple development and parturition in LGR7 knockout mice. Mol Cell Biol 24: 687-696.
47. Kubota Y, Temelcos C, Bathgate RA, Smith KJ, Scott D, Zhao C et al. (2002). The role of insulin 3, testosterone, Mullerian inhibiting substance and relaxin in rat gubernacular growth. Mol Hum Reprod 8: 900-905.
48. Kumagai J, Hsu SY, Matsumi H, Roh JS, Fu P, Wade JD et al. (2002). INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. J Biol Chem 277: 31283-31286.
49. Liu C, Chen J, Sutton S, Roland B, Kuei C, Farmer N et al. (2003a). Identification of relaxin-3/INSL7 as a ligand for GPCR142. J Biol Chem 278: 50765-50770.
50. Liu C, Eriste E, Sutton S, Chen J, Roland B, Kuei C et al. (2003b). Identification of relaxin-3/INSL7 as an endogenous ligand for the orphan G-protein-coupled receptor GPCR135. J Biol Chem 278: 50754-50764.
51. Liu C, Kuei C, Sutton S, Chen J, Bonaventure P, Wu J et al. (2005). INSL5 is a high affinity specific agonist for GPCR142 (GPR100). J Biol Chem 280: 292-300.
52. Loosfelt H, Misrahi M, Atger M, Salesse R, Vu Hai-Luu Thi MT, Jolivet A et al. (1989). Cloning and sequencing of porcine LH-hCG receptor cDNA: variants lacking transmembrane domain. Science 245: 525-528.
53. Luna JJ, Riesewijk A, Horcajadas JA, De Van Os R, Dominguez F, Mosselman S et al. (2004). Gene expression pattern and immunoreactive protein localisation of LGR7 receptor in human endometrium throughout the menstrual cycle. Mol Hum Reprod 10: 85-90.
54. Matsumoto M, Kamohara M, Sugimoto T, Hidaka K, Takasaki J, Saito T et al. (2000). The novel G-protein coupled receptor SALPR shares sequence similarity with somatostatin and angiotensin receptors. Gene 248: 183-189.
55. Mazella J, Tang M, Tseng L (2004). Disparate effects of relaxin and TGFbeta1: relaxin increases, but TGFbeta1 inhibits, the relaxin receptor and the production of IGFBP-1 in human endometrial stromal/decidual cells. Hum Reprod 19: 1513-1518.
56. McGowan BM, Stanley SA, Smith KL, Minnion JS, Donovan J, Thompson EL et al. (2006). Effects of acute and chronic relaxin-3 on food intake and energy expenditure in rats. Regul Pept 136: 72-77.
57. McGowan BM, Stanley SA, Smith KL, White NE, Connolly MM, Thompson EL et al. (2005). Central relaxin-3 administration causes hyperphagia in male Wistar rats. Endocrinology 146: 3295-3300.'
58. Misrahi M, Beau I, Ghinea N, Vannier B, Loosfelt H, Meduri G et al. (1996). The LH/CG and FSH receptors: different molecular forms and intracellular traffic. Mol Cell Endocrinol 125: 161-167.
59. Muda M, He C, Martini PG, Ferraro T, Layfield S, Taylor D et al. (2005). Splice variants of the relaxin and INSL3 receptors reveal unanticipated molecular complexity. Mol Hum Reprod 11: 591-600.
60. Nakamura K, Yamashita S, Omori Y, Minegishi T (2004). A splice variant of the human luteinizing hormone (LH) receptor modulates the expression of wild-type human LH receptor. Mol Endocrinol 18: 1461-1470.
61. Nef S, Parada LF (1999). Cryptorchidism in mice mutant for Insl3. Nat Genet 22: 295-299.
62. Nguyen BT, Dessauer CW (2005). Relaxin stimulates protein kinase C zeta translocation: requirement for cyclic adenosine 3′,5′-monophosphate production. Mol Endocrinol 19: 1012-1023.
63. Nguyen BT, Yang L, Sanborn BM, Dessauer CW (2003). Phosphoinositide 3-kinase activity is required for biphasic stimulation of cyclic adenosine 3′,5′-monophosphate by relaxin. Mol Endocrinol 17: 1075-1084.
64. Nguyen MT, Showalter PR, Timmons CF, Nef S, Parada LF, Baker LA (2002). Effects of orchiopexy on congenitally cryptorchid insulin-3 knockout mice. J Urol 168: 1779-1783; discussion 1783.
65. Nistri S, Bani D (2003). Relaxin receptors and nitric oxide synthases: search for the missing link. Reprod Biol Endocrinol 1: 5.
66. Overbeek PA, Gorlov IP, Sutherland RW, Houston JB, Harrison WR, Boettger-Tong HL et al. (2001). A transgenic insertion causing cryptorchidism in mice. Genesis 30: 26-35.
67. Parsell DA, Mak JY, Amento EP, Unemori EN (1996). Relaxin binds to and elicits a response from cells of the human monocytic cell line, THP-1. J Biol Chem 271: 27936-27941.
68. Rosengren KJ, Lin F, Bathgate RA, Tregear GW, Daly NL, Wade JD et al. (2006). Solution structure and novel insights into the determinants of the receptor specificity of human relaxin-3. J Biol Chem 281: 5845-5851.
69. Samuel CS, Zhao C, Bathgate RA, Bond CP, Burton MD, Parry LJ et al. (2003). Relaxin deficiency in mice is associated with an age-related progression of pulmonary fibrosis. FASEB J 17: 121-123.
70. Samuel CS, Zhao C, Bathgate RA, Du XJ, Summers RJ, Amento EP et al. (2005a). The relaxin gene-knockout mouse: a model of progressive fibrosis. Ann N Y Acad Sci 1041: 173-181.
71. Samuel CS, Zhao C, Yang Q, Wang H, Tian H, Tregear GW et al. (2005b). The relaxin gene knockout mouse: a model of progressive scleroderma. J Invest Dermatol 125: 692-699.
72. Sanborn BM, Kuo HS, Weisbrodt NW, Sherwood OD (1980). The interaction of relaxin with the rat uterus. I. Effect on cyclic nucleotide levels and spontaneous contractile activity. Endocrinology 106: 1210-1215.
73. Scott DJ, Layfield S, Riesewijk A, Morita H, Tregear GW, Bathgate RA (2005a). Characterization of the mouse and rat relaxin receptors. Ann NY Acad Sci 1041: 8-12.
74. Scott DJ, Layfield S, Yan Y, Sudo S, Hsueh AJ, Tregear GW et al. (2006). Characterization of novel splice variants of LGR7 and LGR8 reveals that receptor signaling is mediated by their unique LDLa modules. J Biol Chem 281: 34942-34954.
75. Scott DJ, Tregear GW, Bathgate RA (2005b). LGR7-truncate is a splice variant of the relaxin receptor LGR7 and is a relaxin antagonist in vitro. Ann NY Acad Sci 1041: 22-26.
76. Sudo S, Kumagai J, Nishi S, Layfield S, Ferraro T, Bathgate RA et al. (2003). H3 relaxin is a specific ligand for LGR7 and activates the receptor by interacting with both the ectodomain and the exoloop 2. J Biol Chem 278: 7855-7862.
77. Sutton SW, Bonaventure P, Kuei C, Roland B, Chen J, Nepomuceno D et al. (2005). Distribution of G-protein-coupled receptor (GPCR)135 binding sites and receptor mRNA in the rat brain suggests a role for relaxin-3 in neuroendocrine and sensory processing. Neuroendocrinology 80: 298-307.
78. Tanaka M, Iijima N, Miyamoto Y, Fukusumi S, Itoh Y, Ozawa H et al. (2005). Neurons expressing relaxin 3/INSL 7 in the nucleus incertus respond to stress. Eur J Neurosci 21: 1659-1670.
79. Tena-Sempere M, Manna PR, Huhtaniemi I (1999). Molecular cloning of the mouse follicle-stimulating hormone receptor complementary deoxyribonucleic acid: functional expression of alternatively spliced variants and receptor inactivation by a C566T transition in exon 7 of the coding sequence. Biol Reprod 60: 1515-1527.
80. van der Westhuizen E, Sexton PM, Bathgate RA, Summers RJ (2005). Responses of GPCR135 to Human Gene 3 (H3) Relaxin in CHO-K1 Cells Determined by Microphysiometry. Ann NY Acad Sci 1041: 332-337.
81. Wilkinson TN, Speed TP, Tregear GW, Bathgate RA (2005a). Evolution of the relaxin-like peptide family. BMC Evol Biol 5: 14.
82. Wilkinson TN, Speed TP, Tregear GW, Bathgate RA (2005b). Coevolution of the relaxin-like peptides and their receptors. Ann NY Acad Sci 1041: 534-539.
83. Wilkinson TN, Speed TP, Tregear GW, Bathgate RA (2005c). Evolution of the relaxin-like peptide family: from neuropeptide to reproduction. Ann NY Acad Sci 1041: 530-533.
84. Yan Y, Cai J, Fu P, Layfield S, Ferraro T, Kumagai J et al. (2005). Studies on soluble ectodomain proteins of relaxin (LGR7) and insulin 3 (LGR8) receptors. Ann NY Acad Sci 1041: 35-39.
85. Zhang Q, Liu SH, Erikson M, Lewis M, Unemori E (2002). Relaxin activates the MAP kinase pathway in human endometrial stromal cells. J Cell Biochem 85: 536-544.
86. Zimmerman S, Steding G, Emmen JM, Brinkmann AO, Nayernia K, Holstein AF et al. (1999). Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol 13: 681-691.