Skip to main content

Advertisement

SpringerLink
Log in

Orthosteric, Allosteric and Biased Signalling at the Relaxin-3 Receptor RXFP3

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Relaxin-3 is a neuropeptide that has roles in stress, memory and appetite regulation. The peptide acts on its cognate receptor RXFP3 to induce coupling to inhibitory G proteins to inhibit adenylyl cyclase and activate MAP-kinases such as ERK1/2, p38MAPK and JNK. Other relaxin family peptides can activate the receptor to produce alternative patterns of signalling and there is an allosteric modulator 135PAM1 that displays probe-selectivity. There are now a variety of selective peptide agonists and antagonists that will assist in the determination of the physiological roles of the relaxin-RXFP3 system and its potential as a drug target.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Notes

  1. Probe selectivity—the allosteric modulation by 135PAM1 only occurs with amidated relaxin analogues and not with the native peptides.

References

  1. Wilkinson TN, Speed TP, Tregear GW, Bathgate RA (2005) Evolution of the relaxin-like peptide family. BMC Evol Biol 5:14

    Article  PubMed  PubMed Central  Google Scholar 

  2. Yegorov S, Good-Avila SV, Parry L, Wilson BC (2009) Relaxin family genes in humans and teleosts. Ann N Y Acad Sci 1160:42–44

    Article  CAS  PubMed  Google Scholar 

  3. Wilkinson TN, Speed TP, Tregear GW, Bathgate RA (2005) Coevolution of the relaxin-like peptides and their receptors. Ann N Y Acad Sci 1041:534–539

    Article  CAS  PubMed  Google Scholar 

  4. Bathgate RA, Samuel CS, Burazin TC, Layfield S, Claasz AA, Reytomas IG, Dawson NF, Zhao C, Bond CP, Summers RJ, Parry LJ, Wade JD, Tregear GW (2002) Human relaxin gene 3 (H3) and the equivalent mouse relaxin (M3) gene. Novel members of the relaxin peptide family. J Biol Chem 277:1148–1157

    Article  CAS  PubMed  Google Scholar 

  5. Tanaka M, Iijima N, Miyamoto Y, Fukusumi S, Itoh Y, Ozawa H, Ibata Y (2005) Neurons expressing relaxin 3/INSL 7 in the nucleus incertus respond to stress. Eur J Neurosci 21:1659–1670

    Article  PubMed  Google Scholar 

  6. Banerjee A, Shen PJ, Ma S, Bathgate RA, Gundlach AL (2010) Swim stress excitation of nucleus incertus and rapid induction of relaxin-3 expression via CRF1 activation. Neuropharmacology 58:145–155

    Article  CAS  PubMed  Google Scholar 

  7. Ma S, Bonaventure P, Ferraro T, Shen PJ, Burazin TC, Bathgate RA, Liu C, Tregear GW, Sutton SW, Gundlach AL (2007) Relaxin-3 in GABA projection neurons of nucleus incertus suggests widespread influence on forebrain circuits via G-protein-coupled receptor-135 in the rat. Neuroscience 144:165–190

    Article  CAS  PubMed  Google Scholar 

  8. McGowan BM, Stanley SA, Smith KL, White NE, Connolly MM, Thompson EL, Gardiner JV, Murphy KG, Ghatei MA, Bloom SR (2005) Central relaxin-3 administration causes hyperphagia in male Wistar rats. Endocrinology 146:3295–3300

    Article  CAS  PubMed  Google Scholar 

  9. Ganella DE, Callander GE, Ma S, Bye CR, Gundlach AL, Bathgate RA (2013) Modulation of feeding by chronic rAAV expression of a relaxin-3 peptide agonist in rat hypothalamus. Gene Ther 20:703–716

    Article  CAS  PubMed  Google Scholar 

  10. Ganella DE, Ma S, Gundlach AL (2013) Relaxin-3/RXFP3 signaling and neuroendocrine function—a perspective on extrinsic hypothalamic control. Front Endocrinol 4:128

    Article  Google Scholar 

  11. Ryan PJ, Buchler E, Shabanpoor F, Hossain MA, Wade JD, Lawrence AJ, Gundlach AL (2013) Central relaxin-3 receptor (RXFP3) activation decreases anxiety-and depressive-like behaviours in the rat. Behav Brain Res 244:142–151

    Article  CAS  PubMed  Google Scholar 

  12. Ryan PJ, Kastman HE, Krstew EV, Rosengren KJ, Hossain MA, Churilov L, Wade JD, Gundlach AL, Lawrence AJ (2013) Relaxin-3/RXFP3 system regulates alcohol-seeking. Proc Natl Acad Sci USA 110:20789–20794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Smith CM, Chua BE, Zhang C, Walker AW, Haidar M, Hawkes D, Shabanpoor F, Hossain MA, Wade JD, Rosengren KJ, Gundlach AL (2014) Central injection of relaxin-3 receptor (RXFP3) antagonist peptides reduces motivated food seeking and consumption in C57BL/6 J mice. Behav Brain Res 268:117–126

    Article  CAS  PubMed  Google Scholar 

  14. Halls ML, Bathgate RA, Sutton SW, Dschietzig TB, Summers RJ (2015) International Union of Basic and Clinical Pharmacology. XCV. Recent advances in the understanding of the pharmacology and biological roles of relaxin family peptide receptors 1-4, the receptors for relaxin family peptides. Pharmacol Rev 67:389–440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu C, Chen J, Sutton S, Roland B, Kuei C, Farmer N, Sillard R, Lovenberg TW (2003) Identification of relaxin-3/INSL7 as a ligand for GPCR142. J Biol Chem 278:50765–50770

    Article  CAS  PubMed  Google Scholar 

  16. Liu C, Eriste E, Sutton S, Chen J, Roland B, Kuei C, Farmer N, Jornvall H, Sillard R, Lovenberg TW (2003) Identification of relaxin-3/INSL7 as an endogenous ligand for the orphan G-protein-coupled receptor GPCR135. J Biol Chem 278:50754–50764

    Article  CAS  PubMed  Google Scholar 

  17. Matsumoto M, Kamohara M, Sugimoto T, Hidaka K, Takasaki J, Saito T, Okada M, Yamaguchi T, Furuichi K (2000) The novel G-protein coupled receptor SALPR shares sequence similarity with somatostatin and angiotensin receptors. Gene 248:183–189

    Article  CAS  PubMed  Google Scholar 

  18. Bathgate RA, Halls ML, van der Westhuizen ET, Callander GE, Kocan M, Summers RJ (2013) Relaxin family peptides and their receptors. Physiol Rev 93:405–480

    Article  CAS  PubMed  Google Scholar 

  19. Kuei C, Sutton S, Bonaventure P, Pudiak C, Shelton J, Zhu J, Nepomuceno D, Wu J, Chen J, Kamme F, Seierstad M, Hack MD, Bathgate RA, Hossain MA, Wade JD, Atack J, Lovenberg TW, Liu C (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 282:25425–25435

    Article  CAS  PubMed  Google Scholar 

  20. Hossain MA, Rosengren KJ, Haugaard-Jonsson LM, Zhang S, Layfield S, Ferraro T, Daly NL, Tregear GW, Wade JD, Bathgate RA (2008) The A-chain of human relaxin family peptides has distinct roles in the binding and activation of the different relaxin family peptide receptors. J Biol Chem 283:17287–17297

    Article  CAS  PubMed  Google Scholar 

  21. Bathgate RA, Oh MH, Ling WJ, Kaas Q, Hossain MA, Gooley PR, Rosengren KJ (2013) Elucidation of relaxin-3 binding interactions in the extracellular loops of RXFP3. Front Endocrinol 4:13

    Article  Google Scholar 

  22. Rosengren KJ, Zhang S, Lin F, Daly NL, Scott DJ, Hughes RA, Bathgate RA, Craik DJ, Wade JD (2006) Solution structure and characterization of the LGR8 receptor binding surface of insulin-like peptide 3. J Biol Chem 281:28287–28295

    Article  CAS  PubMed  Google Scholar 

  23. Wu B, Chien EY, Mol CD, Fenalti G, Liu W, Katritch V, Abagyan R, Brooun A, Wells P, Bi FC, Hamel DJ, Kuhn P, Handel TM, Cherezov V, Stevens RC (2010) Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330:1066–1071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Grosse J, Heffron H, Burling K, Akhter Hossain M, Habib AM, Rogers GJ, Richards P, Larder R, Rimmington D, Adriaenssens AA, Parton L, Powell J, Binda M, Colledge WH, Doran J, Toyoda Y, Wade JD, Aparicio S, Carlton MB, Coll AP, Reimann F, O’Rahilly S, Gribble FM (2014) Insulin-like peptide 5 is an orexigenic gastrointestinal hormone. Proc Natl Acad Sci USA 111:11133–11138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhu J, Kuei C, Sutton S, Kamme F, Yu J, Bonaventure P, Atack J, Lovenberg TW, Liu C (2008) Identification of the domains in RXFP4 (GPCR142) responsible for the high affinity binding and agonistic activity of INSL5 at RXFP4 compared to RXFP3 (GPCR135). Eur J Pharmacol 590:43–52

    Article  CAS  PubMed  Google Scholar 

  26. Rosengren KJ, Lin F, Bathgate RA, Tregear GW, Daly NL, Wade JD, Craik DJ (2006) Solution structure and novel insights into the determinants of the receptor specificity of human relaxin-3. J Biol Chem 281:5845–5851

    Article  CAS  PubMed  Google Scholar 

  27. Liu C, Chen J, Kuei C, Sutton S, Nepomuceno D, Bonaventure P, Lovenberg TW (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

    Article  CAS  PubMed  Google Scholar 

  28. Shabanpoor F, Akhter Hossain M, Ryan PJ, Belgi A, Layfield S, Kocan M, Zhang S, Samuel CS, Gundlach AL, Bathgate RA, Separovic F, Wade JD (2012) Minimization of human relaxin-3 leading to high-affinity analogues with increased selectivity for relaxin-family peptide 3 receptor (RXFP3) over RXFP1. J Med Chem 55:1671–1681

    Article  CAS  PubMed  Google Scholar 

  29. Haugaard-Kedstrom 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 133:4965–4974

    Article  CAS  PubMed  Google Scholar 

  30. Baker JG, Hill SJ (2007) Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates. Trends Pharmacol Sci 28:374–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kenakin T, Miller LJ (2010) Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery. Pharmacol Rev 62:265–304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Evans BA, Sato M, Sarwar M, Hutchinson DS, Summers RJ (2010) Ligand-directed signalling at beta-adrenoceptors. Br J Pharmacol 159:1022–1038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Alvarez-Jaimes L, Sutton SW, Nepomuceno D, Motley ST, Cik M, Stocking E, Shoblock J, Bonaventure P (2012) In vitro pharmacological characterization of RXFP3 allosterism: an example of probe dependency. PLoS One 7:e30792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hossain MA, Bathgate RA, Rosengren KJ, Shabanpoor F, Zhang S, Lin F, Tregear GW, Wade JD (2009) The structural and functional role of the B-chain C-terminal arginine in the relaxin-3 peptide antagonist, R3(BDelta23-27)R/I5. Chem Biol Drug Des 73:46–52

    Article  CAS  PubMed  Google Scholar 

  35. 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 77:759–772

    Article  PubMed  Google Scholar 

  36. van der Westhuizen ET, Werry TD, Sexton PM, Summers RJ (2007) The Relaxin Family Peptide Receptor 3 (RXFP3) activates ERK1/2 through a PKC dependent mechanism. Mol Pharmacol 71:1618–1629

    Article  PubMed  Google Scholar 

  37. Morikawa Y, Ueyama E, Senba E (2004) Fasting-induced activation of mitogen-activated protein kinases (ERK/p38) in the mouse hypothalamus. J Neuroendocrinol 16:105–112

    Article  CAS  PubMed  Google Scholar 

  38. Shen CP, Tsimberg Y, Salvadore C, Meller E (2004) Activation of Erk and JNK MAPK pathways by acute swim stress in rat brain regions. BMC Neurosci 5:36

    Article  PubMed  PubMed Central  Google Scholar 

  39. Sasaguri K, Kikuchi M, Hori N, Yuyama N, Onozuka M, Sato S (2005) Suppression of stress immobilization-induced phosphorylation of ERK 1/2 by biting in the rat hypothalamic paraventricular nucleus. Neurosci Lett 383:160–164

    Article  CAS  PubMed  Google Scholar 

  40. Roux PP, Blenis J (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68:320–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252

    Article  CAS  PubMed  Google Scholar 

  42. Price MA, Cruzalegui FH, Treisman R (1996) The p38 and ERK MAP kinase pathways cooperate to activate ternary complex factors and c-fos transcription in response to UV light. EMBO J 15:6552–6563

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Whitmarsh AJ, Davis RJ (1996) Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med 74:589–607

    Article  CAS  PubMed  Google Scholar 

  44. 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 N Y Acad Sci 1041:332–337

    Article  PubMed  Google Scholar 

  45. Kocan M, Sarwar M, Hossain MA, Wade JD, Summers RJ (2014) Signalling profiles of H3 relaxin, H2 relaxin and R3(BDelta23-27)R/I5 acting at the relaxin family peptide receptor 3 (RXFP3). Br J Pharmacol 171:2827–2841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shi L, Shi SQ, Saade GR, Chwalisz K, Garfield RE (2000) Studies of cervical ripening in pregnant rats: effects of various treatments. Mol Hum Reprod 6:382–389

    Article  CAS  PubMed  Google Scholar 

  47. Van der Westhuizen ET (2008) Molecular characterisation of human and mouse relaxin-3 receptors (RXFP3) in recombinant and endogenously expressing cell lines. PhD Thesis, Monash University, Melbourne

  48. Luttrell LM, Gesty-Palmer D (2010) Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol Rev 62:305–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cottrell GS, Padilla BE, Amadesi S, Poole DP, Murphy JE, Hardt M, Roosterman D, Steinhoff M, Bunnett NW (2009) Endosomal endothelin-converting enzyme-1: a regulator of beta-arrestin-dependent ERK signaling. J Biol Chem 284:22411–22425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

RJS is supported by National Health and Medical Research Council of Australia Program Grant 1055134.

Author information

Authors and Affiliations

  1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, Melbourne, VIC, 3052, Australia

    Martina Kocan, Sheng Yu Ang & Roger J. Summers

Authors
  1. Martina Kocan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sheng Yu Ang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roger J. Summers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roger J. Summers.

Additional information

Special Issue: In Honor of Philip Beart.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kocan, M., Ang, S.Y. & Summers, R.J. Orthosteric, Allosteric and Biased Signalling at the Relaxin-3 Receptor RXFP3. Neurochem Res 41, 610–619 (2016). https://doi.org/10.1007/s11064-015-1701-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-015-1701-3

Keywords

Search

Navigation