Relaxin family peptide receptors
More information on this family may be found on the IUPHAR-DB family and introduction pages.
Relaxin family peptide receptors (RXFP, nomenclature as recommended by the NC-IUPHAR committee on relaxin family peptide receptors, [1]) may be divided into two groups RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are a number of heterodimeric peptide hormones analogous to insulin: H1 relaxin [ENSG00000107018], H2 relaxin [ENSG00000107014], H3 relaxin [also known as INSL7, ENSG00000171136], insulin-like peptide 3 (INSL3) [OTTHUMG00000070952*] and INSL5 [ENSG00000172410].
Species homologues of relaxin have distinct pharmacology – H2 relaxin interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [25] and porcine relaxin may have a higher efficacy than H2 relaxin [6]. H3 relaxin has differential affinity for RXFP2 receptors between species; mouse and rat RXFP2 and RXFP3 have a higher affinity for H3 relaxin [24]. At least two binding sites have been identified on the RXFP1 and RXFP2 receptors: a high-affinity site in the leucine-rich repeat region of the ectodomain and a somewhat lower-affinity site located in the surface loops of the transmembrane [6,29]. The unique N-terminal LDLa module of RXFP1 and RXFP2 is essential for receptor signalling [26].
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Receptors 
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Bathgate, R. A., Ivell, R., Sanborn, B. M., Sherwood, O. D. and Summers, R. J. (2006) International Union of Pharmacology LVII: recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev, 58: 7-31. [PMID:16507880]
Callander, GE; Bathgate, RA. (2010) Relaxin family peptide systems and the central nervous system. Cell. Mol. Life Sci., 67 (14): 2327-41. [PMID:20213277]
Chan, LJ; Hossain, MA; Samuel, CS; Separovic, F; Wade, JD. (2011) The relaxin peptide family--structure, function and clinical applications. Protein Pept. Lett., 18 (3): 220-9. [PMID:20858209]
Du, XJ; Bathgate, RA; Samuel, CS; Dart, AM; Summers, RJ. (2010) Cardiovascular effects of relaxin: from basic science to clinical therapy. Nat Rev Cardiol, 7 (1): 48-58. [PMID:19935741]
Grossman, J; Frishman, WH. (2010) Relaxin: a new approach for the treatment of acute congestive heart failure. Cardiol Rev, 18 (6): 305-12. [PMID:20926940]
Halls, ML; van der Westhuizen, ET; Bathgate, RA; Summers, RJ. (2007) Relaxin family peptide receptors--former orphans reunite with their parent ligands to activate multiple signalling pathways. Br. J. Pharmacol., 150 (6): 677-91. [PMID:17293890]
Hoffmann, FG; Opazo, JC. (2011) Evolution of the relaxin/insulin-like gene family in placental mammals: implications for its early evolution. J. Mol. Evol., 72 (1): 72-9. [PMID:21082170]
Ivell, R; Kotula-Balak, M; Glynn, D; Heng, K; Anand-Ivell, R. (2011) Relaxin family peptides in the male reproductive system--a critical appraisal. Mol. Hum. Reprod., 17 (2): 71-84. [PMID:20952422]
Kong, RC; Shilling, PJ; Lobb, DK; Gooley, PR; Bathgate, RA. (2010) Membrane receptors: structure and function of the relaxin family peptide receptors. Mol. Cell. Endocrinol., 320 (1-2): 1-15. [PMID:20138959]
van der Westhuizen, ET; Halls, ML; Samuel, CS; Bathgate, RA; Unemori, EN; Sutton, SW; Summers, RJ. (2008) Relaxin family peptide receptors--from orphans to therapeutic targets. Drug Discov. Today, 13 (15-16): 640-51. [PMID:18675759]
Van Der Westhuizen, ET; Summers, RJ; Halls, ML; Bathgate, RA; Sexton, PM. (2007) Relaxin receptors--new drug targets for multiple disease states. Curr Drug Targets, 8 (1): 91-104. [PMID:17266534]
1. Bathgate, R. A., Ivell, R., Sanborn, B. M., Sherwood, O. D. and Summers, R. J. (2006) International Union of Pharmacology LVII: recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev, 58: 7-31. [PMID:16507880]
2. Büllesbach, E. E. and Schwabe, C. (2005) LGR8 signal activation by the relaxin-like factor. J Biol Chem, 280: 14586-14590. [PMID:15708846]
3. Del Borgo, M. P., Hughes, R. A., Bathgate, R. A., Lin, F., Kawamura, K. and Wade, J. D. (2006) Analogs of insulin-like peptide 3 (INSL3) B-chain are LGR8 antagonists in vitro and in vivo. J Biol Chem, : 727-729. [PMID:16547350]
4. Ferlin, A; Simonato, M; Bartoloni, L; Rizzo, G; Bettella, A; Dottorini, T; Dallapiccola, B; Foresta, C. (2003) The INSL3-LGR8/GREAT ligand-receptor pair in human cryptorchidism. J. Clin. Endocrinol. Metab., 88 (9): 4273-9. [PMID:12970298]
5. Halls, M. L., Bathgate, R. A. and Summers, R. J. (2006) Relaxin family peptide receptors, RXFP1 and RXFP2, modulate cAMP signalling by distinct mechanisms. Mol Pharmacol, : -. [PMID:16569707]
6. Halls, M. L., Bond, C. P., Sudo, S., Kumagai, J., Ferraro, T., Layfield, S., Bathgate, R. A. and Summers, R. J. (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. [PMID:15649866]
7. Halls, ML; Cooper, DM. (2010) Sub-picomolar relaxin signalling by a pre-assembled RXFP1, AKAP79, AC2, beta-arrestin 2, PDE4D3 complex. EMBO J., 29 (16): 2772-87. [PMID:20664520]
8. Halls, ML; Hewitson, TD; Moore, XL; Du, XJ; Bathgate, RA; Summers, RJ. (2009) Relaxin activates multiple cAMP signaling pathway profiles in different target cells. Ann. N. Y. Acad. Sci., 1160: 108-11. [PMID:19416169]
9. Halls, ML; van der Westhuizen, ET; Bathgate, RA; Summers, RJ. (2007) Relaxin family peptide receptors--former orphans reunite with their parent ligands to activate multiple signalling pathways. Br. J. Pharmacol., 150 (6): 677-91. [PMID:17293890]
10. Halls, ML; van der Westhuizen, ET; Wade, JD; Evans, BA; Bathgate, RA; Summers, RJ. (2009) Relaxin family peptide receptor (RXFP1) coupling to G(alpha)i3 involves the C-terminal Arg752 and localization within membrane Raft Microdomains. Mol. Pharmacol., 75 (2): 415-28. [PMID:19029286]
11. Haugaard-Kedström, LM; Shabanpoor, F; Hossain, MA; Clark, RJ; Ryan, PJ; Craik, DJ; Gundlach, AL; Wade, JD; Bathgate, RA; Rosengren, KJ. (2011) Design, synthesis, and characterization of a single-chain peptide antagonist for the relaxin-3 receptor RXFP3. J. Am. Chem. Soc., 133 (13): 4965-74. [PMID:21384867]
12. Hossain, MA; Rosengren, KJ; Zhang, S; Bathgate, RA; Tregear, GW; van Lierop, BJ; Robinson, AJ; Wade, JD. (2009) Solid phase synthesis and structural analysis of novel A-chain dicarba analogs of human relaxin-3 (INSL7) that exhibit full biological activity. Org. Biomol. Chem., 7 (8): 1547-53. [PMID:19343240]
13. Hossain, MA; Samuel, CS; Binder, C; Hewitson, TD; Tregear, GW; Wade, JD; Bathgate, RA. (2010) The chemically synthesized human relaxin-2 analog, B-R13/17K H2, is an RXFP1 antagonist. Amino Acids, 39 (2): 409-16. [PMID:20043231]
14. Hsu, S. Y., Kudo, M., Chen, T., Nakabayashi, K., Bhalla, A., van der Spek, P. J., van Duin, M. and Hsueh, A. J. (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. [PMID:10935549]
15. Hsu, S. Y., Nakabayashi, K., Nishi, S., Kumagai, J., Kudo, M., Sherwood, O. D. and Hsueh, A. J. (2002) Activation of orphan receptors by the hormone relaxin. Science, 295: 671-674. [PMID:11809971]
16. Kuei, C; Sutton, S; Bonaventure, P; Pudiak, C; Shelton, J; Zhu, J; Nepomuceno, D; Wu, J; Chen, J; Kamme, F; et al.. (2007) R3(BDelta23 27)R/I5 chimeric peptide, a selective antagonist for GPCR135 and GPCR142 over relaxin receptor LGR7: in vitro and in vivo characterization. J. Biol. Chem., 282 (35): 25425-35. [PMID:17606621]
17. Kumagai, J., Hsu, S. Y., Matsumi, H., Roh, J. S., Fu, P., Wade, J. D., Bathgate, R. A. and Hsueh, A. J. (2002) INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. J Biol Chem, 277: 31283-31286. [PMID:12114498]
18. Liu, C., Chen, J., Kuei, C., Sutton, S., Nepomuceno, D., Bonaventure, P. and Lovenberg, T. W. (2005) Relaxin-3/insulin-like peptide 5 chimeric peptide, a selective ligand for G protein-coupled receptor (GPCR)135 and GPCR142 over leucine-rich repeat-containing G protein-coupled receptor 7. Mol Pharmacol, 67: 231-240. [PMID:15465925]
19. Liu, C., Chen, J., Sutton, S., Roland, B., Kuei, C., Farmer, N., Sillard, R. and Lovenberg, T. W. (2003) Identification of relaxin-3/INSL7 as a ligand for GPCR142. J Biol Chem, 278: 50765-50770. [PMID:14522967]
20. Liu, C., Eriste, E., Sutton, S., Chen, J., Roland, B., Kuei, C., Farmer, N., Jörnvall, H., Sillard, R. and Lovenberg, T. W. (2003) Identification of relaxin-3/INSL7 as an endogenous ligand for the orphan G-protein-coupled receptor GPCR135. J Biol Chem, 278: 50754-50764. [PMID:14522968]
21. Liu, C., Kuei, C., Sutton, S., Chen, J., Bonaventure, P., Wu, J., Nepomuceno, D., Kamme, F., Tran, D. T., Zhu, J., Wilkinson, T., Bathgate, R., Eriste, E., Sillard, R. and Lovenberg, T. W. (2005) INSL5 is a high affinity specific agonist for GPCR142 (GPR100). J Biol Chem, 280: 292-300. [PMID:15525639]
22. Matsumoto, M., Kamohara, M., Sugimoto, T., Hidaka, K., Takasaki, J., Saito, T., Okada, M., Yamaguchi, T. and Furuichi, K. (2000) The novel G-protein coupled receptor SALPR shares sequence similarity with somatostatin and angiotensin receptors. Gene, 248: 183-189. [PMID:10806363]
23. Muda, M., He, C., Martini, P. G., Ferraro, T., Layfield, S., Taylor, D., Chevrier, C., Schweickhardt, R., Kelton, C., Ryan, P. L. and Bathgate, R. A. (2005) Splice variants of the relaxin and INSL3 receptors reveal unanticipated molecular complexity. Mol Hum Reprod, 11: 591-600. [PMID:16051677]
24. Scott, D. J., Fu, P., Shen, P. J., Gundlach, A., Layfield, S., Riesewijk, A., Tomiyama, H., Hutson, J. M., Tregear, G. W. and Bathgate, R. A. (2005) Characterization of the rat INSL3 receptor. Ann N Y Acad Sci, 1041: 13-16. [PMID:15956681]
25. Scott, DJ; Layfield, S; Riesewijk, A; Morita, H; Tregear, GW; Bathgate, RA. (2005) Characterization of the mouse and rat relaxin receptors. Ann. N. Y. Acad. Sci., 1041: 8-12. [PMID:15956680]
26. Scott, DJ; Layfield, S; Yan, Y; Sudo, S; Hsueh, AJ; Tregear, GW; Bathgate, RA. (2006) Characterization of novel splice variants of LGR7 and LGR8 reveals that receptor signaling is mediated by their unique low density lipoprotein class A modules. J. Biol. Chem., 281 (46): 34942-54. [PMID:16963451]
27. Shabanpoor, F; Hughes, RA; Bathgate, RA; Zhang, S; Scanlon, DB; Lin, F; Hossain, MA; Separovic, F; Wade, JD. (2008) Solid-phase synthesis of europium-labeled human INSL3 as a novel probe for the study of ligand-receptor interactions. Bioconjug. Chem., 19 (7): 1456-63. [PMID:18529069]
28. Shabanpoor, F; Zhang, S; Hughes, RA; Hossain, MA; Layfield, S; Ferraro, T; Bathgate, RA; Separovic, F; Wade, JD. (2011) Design and development of analogues of dimers of insulin-like peptide 3 B-chain as high-affinity antagonists of the RXFP2 receptor. Biopolymers, 96 (1): 81-7. [PMID:20560146]
29. Sudo, S., Kumagai, J., Nishi, S., Layfield, S., Ferraro, T., Bathgate, R. A. and Hsueh, A. J. (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. [PMID:12506116]
30. van der Westhuizen, ET; Christopoulos, A; Sexton, PM; Wade, JD; Summers, RJ. (2010) H2 relaxin is a biased ligand relative to H3 relaxin at the relaxin family peptide receptor 3 (RXFP3). Mol. Pharmacol., 77 (5): 759-72. [PMID:20159943]
31. Van Der Westhuizen, ET; Summers, RJ; Halls, ML; Bathgate, RA; Sexton, PM. (2007) Relaxin receptors--new drug targets for multiple disease states. Curr Drug Targets, 8 (1): 91-104. [PMID:17266534]
32. Wilkinson, T. N., Speed, T. P., Tregear, G. W. and Bathgate, R. A. (2005) Evolution of the relaxin-like peptide family. BMC Evol Biol, 5: 14-14. [PMID:15707501]
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Mutations in INSL3 and LGR8 (RXFP2) have been reported in populations of patients with cryptorchidism [4]. Numerous splice variants of the human RXFP1 and RXFP2 receptors have been identified, none of which bind relaxin family peptides [23]. Splice variants of RXFP1 encoding the N-terminal LDLa module act as antagonists of RXFP1 signalling [24,26]. cAMP elevation appears to be a major signalling pathway for RXFP1 and RXFP2 [14-15], but RXFP1 also activates MAP kinases, nitric oxide signalling and interacts with tyrosine kinases and glucocorticoid receptors [9]. RXFP1 signalling involves lipid rafts, residues in the C-terminus of the receptor and activation of phosphatidylinositol-3-kinase [10]. More recent studies provide evidence that RXFP1 is pre-assembled in signalosomes with other signalling proteins including Gαs, Gβγ and adenyl cyclase 2 that display constitutive activity and are exquisitely sensitive to sub-picomolar concentrations of relaxin [7]. The cAMP signalling pattern is highly dependent on the cell type in which RXFP1 is expressed [8].
H3 relaxin acts as an agonist at both RXFP3 and RXFP4 whereas INSL5 is an agonist at RXFP4 and an antagonist at RXFP3. Unlike RXFP1 and RXFP2 both RXFP3 and RXFP4 are encoded by a single exon and therefore no splice variants exist. The rat RXFP3 sequence has two potential start codons that encode RXFP3L and RXFP3S with the longer variant having an additional 7 amino-acids at the N-terminus. It is not known which variant is expressed. Rat and dog RXFP4 sequences are pseudogenes [32]. Recent studies suggest that H2 relaxin also interacts with RXFP3 to cause a pattern of activation of signalling pathways that are a subset of those activated by H3 relaxin. The two patterns of signaling observed in several cell types expressing RXFP3 are strong inhibition of forskolin-stimulated cAMP accumulation, ERK1/2 activation and nuclear factor NFκ-B reporter gene activation with H3 relaxin, and weaker activity with H2 relaxin, porcine relaxin, or insulin-like peptide 3 (INSL3) and a strong stimulation of activator protein (AP)-1 reporter genes with H2 relaxin, and weaker activation with H3 relaxin or porcine relaxin [30]. Two distinct ligand binding sites were also identified on RXFP3-expressing cells using two different radioligands. [125I]H3-B/INSL5 A chimera binds with high affinity with competition by H3 relaxin or a H3 relaxin (B chain) peptide, whereas [125I]H2 relaxin binding is competed for by H2 relaxin, H3 relaxin, or INSL3 and weakly by porcine relaxin. Thus at RXFP3, H2 relaxin is a biased ligand compared to the cognate ligand H3 relaxin.