Relaxin family peptide receptors (RXFP, nomenclature as agreed by the NC-IUPHAR Subcommittee on Relaxin family peptide receptors [4,24]) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are heterodimeric peptide hormones structurally related to insulin: relaxin-1 (RLN1, P04808), relaxin (RLN2, P04090), relaxin-3 (RLN3, Q8WXF3) (also known as INSL7), insulin-like peptide 3 (INSL3 (INSL3, P51460)) and INSL5 (INSL5, Q9Y5Q6). Species homologues of relaxin have distinct pharmacology and relaxin (RLN2, P04090) interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [69]. Relaxin-3 (RLN3, Q8WXF3) is the ligand for RXFP3 but it also binds to RXFP1 and RXFP4 and has differential affinity for RXFP2 between species [68]. INSL5 (INSL5, Q9Y5Q6) is the ligand for RXFP4 but is a weak antagonist of RXFP3. Relaxin (RLN2, P04090) and INSL3 (INSL3, P51460) have multiple complex binding interactions with RXFP1 [72] and RXFP2 [31] which direct the N-terminal LDLa modules of the receptors together with a linker domain to act as a tethered ligand to direct receptor signaling [70]. INSL5 (INSL5, Q9Y5Q6) and relaxin-3 (RLN3, Q8WXF3) interact with their receptors using distinct residues in their B-chains for binding, and activation, respectively [40,88].

Relaxin (RLN2, P04090) is the cognate peptide ligand for RXFP1 and is a potential treatment for heart failure [16]. Relaxin has vasodilatory, anti-fibrotic, angiogenic, anti-apoptotic and anti-inflammatory effects. A small molecule allosteric agonist ML290 has been developed [78,90], that displays anti-fibrotic properties [44], and a relaxin B-chain mimetic peptide B7-33 has been developed which has cell specific signaling properties [33]. The antifibrotic actions of relaxin are dependent on the angiotensin receptor AT₂ [8] and are blocked by either AT₁ or AT₂ receptor antagonists. INSL3 (INSL3, P51460) is the cognate peptide for RXFP2 and is a circulating hormone that in males is essential for testicular descent in utero [62] and in females has important roles in ovarian follicle function [42]. In adults, INSL3 has potential roles in testicular function [43] and the musculo-skeletal system [10]. RXFP2 is also present in brain, associated with cortico-thalamic motor circuits [71]. cAMP elevation is the major signalling pathway for both RXFP1 and RXFP2 [37-38], but RXFP1 also activates MAP kinases, nitric oxide signalling, and tyrosine kinase phosphorylation; and relaxin can interact with glucocorticoid receptors [26]. RXFP1 displays ultra-sensitive responses to sub picomolar levels of relaxin [9]. Receptor expression profiles suggest that RXFP3 is a brain neuropeptide receptor [56-57,80] and RXFP4 a gut hormone receptor [19]. The brain relaxin-3/RXFP3 system modulates feeding [18-19,29,73,79] via effects in hypothalamus [11,18,45-46], anxiety [59,66-67,91], reward and motivated, goal-directed behaviours [32,66,85], and spatial and social memory [1,21-22]. Of the other relaxin peptides, relaxin-3 (RLN3, Q8WXF3) is an agonist at RXFP3 and RXFP4 whereas INSL5 (INSL5, Q9Y5Q6) is an agonist at RXFP4 and a weak antagonist at RXFP3. Single chain peptide agonists and antagonists have been developed for RXFP3 [28,49] and a small molecular weight agonist active at RXFP3 and RXFP4 [12]. INSL5 (INSL5, Q9Y5Q6) is secreted from enteroendocrine L cells and the INSL5/RXFP4 system affects food intake [20], colon motility [15] and glucose homeostasis [55]. RXFP3 and RXFP4 couple to G_i/o and inhibit adenylyl cyclase [54,82], and also cause Erk1/2 phosphorylation [82]. RXFP4 also causes phosphorylation of p38MAPK, Akt and S6RP [3] and GLP-1 secretion in vitro [2]. There is evidence that at RXFP3, relaxin (RLN2, P04090) is a biased ligand compared to the cognate ligand relaxin-3 (RLN3, Q8WXF3) [82].

* Key recommended reading is highlighted with an asterisk

* Bathgate RA, Halls ML, van der Westhuizen ET, Callander GE, Kocan M, Summers RJ. (2013) Relaxin family peptides and their receptors. Physiol Rev, 93 (1): 405-80. [PMID:23303914]

Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ. (2006) International Union of Pharmacology LVII: recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev, 58 (1): 7-31. [PMID:16507880]

* Bathgate RAD, Kocan M, Scott DJ, Hossain MA, Good SV, Yegorov S, Bogerd J, Gooley PR. (2018) The relaxin receptor as a therapeutic target - perspectives from evolution and drug targeting. Pharmacol Ther, 187: 114-132. [PMID:29458108]

Callander GE, Bathgate RA. (2010) Relaxin family peptide systems and the central nervous system. Cell Mol Life Sci, 67 (14): 2327-41. [PMID:20213277]

* 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]

* Esteban-Lopez M, Agoulnik AI. (2020) Diverse functions of insulin-like 3 peptide. J Endocrinol, 247 (1): R1-R12. [PMID:32813485]

* Gil-Miravet I, Mañas-Ojeda A, Ros-Bernal F, Castillo-Gómez E, Albert-Gascó H, Gundlach AL, Olucha-Bordonau FE. (2021) Involvement of the Nucleus Incertus and Relaxin-3/RXFP3 Signaling System in Explicit and Implicit Memory. Front Neuroanat, 15: 637922. [PMID:33867946]

* 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 (2): 389-440. [PMID:25761609]

* 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]

* Klonisch T. (2019) Editorial to the mini-review series on relaxin, related peptides and receptors?. Mol Cell Endocrinol, 487: 1. [PMID:30831203]

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]

* Samuel CS, Bennett RG. (2022) Relaxin as an anti-fibrotic treatment: Perspectives, challenges and future directions. Biochem Pharmacol, 197: 114884. [PMID:34968489]

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]

1. Albert-Gasco H, Sanchez-Sarasua S, Ma S, García-Díaz C, Gundlach AL, Sanchez-Perez AM, Olucha-Bordonau FE. (2019) Central relaxin-3 receptor (RXFP3) activation impairs social recognition and modulates ERK-phosphorylation in specific GABAergic amygdala neurons. Brain Struct Funct, 224 (1): 453-469. [PMID:30368554]

2. Ang SY, Evans BA, Poole DP, Bron R, DiCello JJ, Bathgate RAD, Kocan M, Hutchinson DS, Summers RJ. (2018) INSL5 activates multiple signalling pathways and regulates GLP-1 secretion in NCI-H716 cells. J Mol Endocrinol, 60 (3): 213-224. [PMID:29535183]

3. Ang SY, Hutchinson DS, Patil N, Evans BA, Bathgate RAD, Halls ML, Hossain MA, Summers RJ, Kocan M. (2017) Signal transduction pathways activated by insulin-like peptide 5 at the relaxin family peptide RXFP4 receptor. Br J Pharmacol, 174 (10): 1077-1089. [PMID:27243554]

4. Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ. (2006) International Union of Pharmacology LVII: recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev, 58 (1): 7-31. [PMID:16507880]

5. Belgi A, Hossain MA, Shabanpoor F, Chan L, Zhang S, Bathgate RA, Tregear GW, Wade JD. (2011) Structure and function relationship of murine insulin-like peptide 5 (INSL5): free C-terminus is essential for RXFP4 receptor binding and activation. Biochemistry, 50 (39): 8352-61. [PMID:21866895]

6. Büllesbach EE, Schwabe C. (2005) LGR8 signal activation by the relaxin-like factor. J Biol Chem, 280 (15): 14586-90. [PMID:15708846]

7. Chen Y, Zhou Q, Wang J, Xu Y, Wang Y, Yan J, Wang Y, Zhu Q, Zhao F, Li C et al.. (2023) Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4). Nat Commun, 14 (1): 492. [PMID:36717591]

8. Chow BS, Kocan M, Bosnyak S, Sarwar M, Wigg B, Jones ES, Widdop RE, Summers RJ, Bathgate RA, Hewitson TD et al.. (2014) Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis. Kidney Int, 86 (1): 75-85. [PMID:24429402]

9. Civciristov S, Halls ML. (2019) Signalling in response to sub-picomolar concentrations of active compounds: Pushing the boundaries of GPCR sensitivity. Br J Pharmacol, 176 (14): 2382-2401. [PMID:30801691]

10. De Toni L, Agoulnik AI, Sandri M, Foresta C, Ferlin A. (2019) INSL3 in the muscolo-skeletal system. Mol Cell Endocrinol, 487: 12-17. [PMID:30625346]

11. de Ávila C, Chometton S, Lenglos C, Calvez J, Gundlach AL, Timofeeva E. (2018) Differential effects of relaxin-3 and a selective relaxin-3 receptor agonist on food and water intake and hypothalamic neuronal activity in rats. Behav Brain Res, 336: 135-144. [PMID:28864207]

12. DeChristopher B, Park SH, Vong L, Bamford D, Cho HH, Duvadie R, Fedolak A, Hogan C, Honda T, Pandey P et al.. (2019) Discovery of a small molecule RXFP3/4 agonist that increases food intake in rats upon acute central administration. Bioorg Med Chem Lett, 29 (8): 991-994. [PMID:30824200]

13. 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,: 727-729. [PMID:16547350]

14. Devarakonda T, Mauro AG, Guzman G, Hovsepian S, Cain C, Das A, Praveen P, Hossain MA, Salloum FN. (2020) B7-33, a Functionally Selective Relaxin Receptor 1 Agonist, Attenuates Myocardial Infarction-Related Adverse Cardiac Remodeling in Mice. J Am Heart Assoc, 9 (8): e015748. [PMID:32295457]

15. Diwakarla S, Bathgate RAD, Zhang X, Hossain MA, Furness JB. (2020) Colokinetic effect of an insulin-like peptide 5-related agonist of the RXFP4 receptor. Neurogastroenterol Motil, 32 (5): e13796. [PMID:31989750]

16. Dschietzig TB. (2019) Relaxin-2 for heart failure with preserved ejection fraction (HFpEF): Rationale for future clinical trials. Mol Cell Endocrinol, 487: 54-58. [PMID:30659842]

17. Esteban-Lopez M, Wilson KJ, Myhr C, Kaftanovskaya EM, Henderson MJ, Southall NT, Xu X, Wang A, Hu X, Barnaeva E et al.. (2022) Discovery of small molecule agonists of the Relaxin Family Peptide Receptor 2. Commun Biol, 5 (1): 1183. [PMID:36333465]

18. 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 (7): 703-16. [PMID:23135160]

19. Ganella DE, Ryan PJ, Bathgate RA, Gundlach AL. (2012) Increased feeding and body weight gain in rats after acute and chronic activation of RXFP3 by relaxin-3 and receptor-selective peptides: functional and therapeutic implications. Behav Pharmacol, 23 (5-6): 516-25. [PMID:22854307]

20. Grosse J, Heffron H, Burling K, Akhter Hossain M, Habib AM, Rogers GJ, Richards P, Larder R, Rimmington D, Adriaenssens AA et al.. (2014) Insulin-like peptide 5 is an orexigenic gastrointestinal hormone. Proc Natl Acad Sci USA, 111 (30): 11133-8. [PMID:25028498]

21. Haidar M, Guèvremont G, Zhang C, Bathgate RAD, Timofeeva E, Smith CM, Gundlach AL. (2017) Relaxin-3 inputs target hippocampal interneurons and deletion of hilar relaxin-3 receptors in "floxed-RXFP3" mice impairs spatial memory. Hippocampus, 27 (5): 529-546. [PMID:28100033]

22. Haidar M, Tin K, Zhang C, Nategh M, Covita J, Wykes AD, Rogers J, Gundlach AL. (2019) Septal GABA and Glutamate Neurons Express RXFP3 mRNA and Depletion of Septal RXFP3 Impaired Spatial Search Strategy and Long-Term Reference Memory in Adult Mice. Front Neuroanat, 13: 30. [PMID:30906254]

23. Halls ML, Bathgate RA, Summers RJ. (2006) Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP signaling by distinct mechanisms. Mol Pharmacol, 70 (1): 214-26. [PMID:16569707]

24. 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 (2): 389-440. [PMID:25761609]

25. Halls ML, Bond CP, Sudo S, Kumagai J, Ferraro T, Layfield S, Bathgate RA, Summers RJ. (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 (2): 677-87. [PMID:15649866]

26. 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]

27. 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]

28. Haugaard-Kedström LM, Lee HS, Jones MV, Song A, Rathod V, Hossain MA, Bathgate RAD, Rosengren KJ. (2018) Binding conformation and determinants of a single-chain peptide antagonist at the relaxin-3 receptor RXFP3. J Biol Chem, 293 (41): 15765-15776. [PMID:30131342]

29. 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]

30. Haugaard-Kedström LM, Wong LL, Bathgate RA, Rosengren KJ. (2015) Synthesis and pharmacological characterization of a europium-labelled single-chain antagonist for binding studies of the relaxin-3 receptor RXFP3. Amino Acids, 47 (6): 1267-71. [PMID:25792111]

31. Hoare BL, Bruell S, Sethi A, Gooley PR, Lew MJ, Hossain MA, Inoue A, Scott DJ, Bathgate RAD. (2019) Multi-Component Mechanism of H2 Relaxin Binding to RXFP1 through NanoBRET Kinetic Analysis. iScience, 11: 93-113. [PMID:30594862]

32. Hosken IT, Sutton SW, Smith CM, Gundlach AL. (2015) Relaxin-3 receptor (Rxfp3) gene knockout mice display reduced running wheel activity: Implications for role of relaxin-3/RXFP3 signalling in sustained arousal. Behav Brain Res, 278: 167-75. [PMID:25257104]

33. Hossain MA, Kocan M, Yao ST, Royce SG, Nair VB, Siwek C, Patil NA, Harrison IP, Rosengren KJ, Selemidis S et al.. (2016) A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1. Chem Sci, 7 (6): 3805-3819. [PMID:30155023]

34. Hossain MA, Kocan M, Yao ST, Royce SG, Nair VB, Siwek C, Patil NA, Harrison IP, Rosengren KJ, Selemidis S et al.. (2016) A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1. Chem Sci, 7 (6): 3805-3819. [PMID:30155023]

35. Hossain MA, Rosengren KJ, Haugaard-Jönsson 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 (25): 17287-97. [PMID:18434306]

36. 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]

37. Hsu SY, Kudo M, Chen T, Nakabayashi K, Bhalla A, van der Spek PJ, van Duin M, Hsueh AJ. (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 (8): 1257-71. [PMID:10935549]

38. Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ. (2002) Activation of orphan receptors by the hormone relaxin. Science, 295 (5555): 671-4. [PMID:11809971]

39. Hu MJ, Shao XX, Li HZ, Nie WH, Wang JH, Liu YL, Xu ZG, Guo ZY. (2018) Development of a novel ligand binding assay for relaxin family peptide receptor 3 and 4 using NanoLuc complementation. Amino Acids, 50 (8): 1111-1119. [PMID:29770870]

40. Hu MJ, Wei D, Shao XX, Wang JH, Liu YL, Xu ZG, Guo ZY. (2017) Interaction mechanism of insulin-like peptide 5 with relaxin family peptide receptor 4. Arch Biochem Biophys, 619: 27-34. [PMID:28274616]

41. Illiano S, Poirier B, Minoletti C, Pasquier O, Riva L, Chenede X, Menguy I, Guillotel M, Prigent P, Le Claire S et al.. (2022) Characterization of a new potent and long-lasting single chain peptide agonist of RXFP1 in cells and in vivo translational models. Sci Rep, 12 (1): 20435. [PMID:36443381]

42. Ivell R, Anand-Ivell R. (2018) Insulin-like peptide 3 (INSL3) is a major regulator of female reproductive physiology. Hum Reprod Update, 24 (6): 639-651. [PMID:30204868]

43. 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]

44. Kaftanovskaya EM, Ng HH, Soula M, Rivas B, Myhr C, Ho BA, Cervantes BA, Shupe TD, Devarasetty M, Hu X et al.. (2019) Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis. FASEB J, 33 (11): 12435-12446. [PMID:31419161]

45. Kania A, Gugula A, Grabowiecka A, de Ávila C, Blasiak T, Rajfur Z, Lewandowski MH, Hess G, Timofeeva E, Gundlach AL et al.. (2017) Inhibition of oxytocin and vasopressin neuron activity in rat hypothalamic paraventricular nucleus by relaxin-3-RXFP3 signalling. J Physiol (Lond.), 595 (11): 3425-3447. [PMID:28098344]

46. Kania A, Szlaga A, Sambak P, Gugula A, Blasiak E, Micioni Di Bonaventura MV, Hossain MA, Cifani C, Hess G, Gundlach AL et al.. (2020) RLN3/RXFP3 Signaling in the PVN Inhibits Magnocellular Neurons via M-like Current Activation and Contributes to Binge Eating Behavior. J Neurosci, 40 (28): 5362-5375. [PMID:32532885]

47. 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]

48. Kumagai J, Hsu SY, Matsumi H, Roh JS, Fu P, Wade JD, Bathgate RA, Hsueh AJ. (2002) INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. J Biol Chem, 277 (35): 31283-6. [PMID:12114498]

49. Lee HS, Postan M, Song A, Clark RJ, Bathgate RAD, Haugaard-Kedström LM, Rosengren KJ. (2020) Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds. Front Chem, 8: 87. [PMID:32133341]

50. Lin G, Feng Y, Cai X, Zhou C, Shao L, Chen Y, Chen L, Liu Q, Zhou Q, Bathgate RAD et al.. (2021) High-Throughput Screening Campaign Identified a Potential Small Molecule RXFP3/4 Agonist. Molecules, 26 (24): 7511. [PMID:34946593]

51. Lin GY, Lin L, Cai XQ, Dai AT, Zhu Y, Li J, Liu Q, Yang DH, Bathgate RAD, Wang MW. (2020) High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4. Acta Pharmacol Sin, 41 (10): 1328-1336. [PMID:32235863]

52. 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 (1): 231-40. [PMID:15465925]

53. 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 (50): 50765-70. [PMID:14522967]

54. Liu C, Eriste E, Sutton S, Chen J, Roland B, Kuei C, Farmer N, Jörnvall 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 (50): 50754-64. [PMID:14522968]

55. Luo X, Li T, Zhu Y, Dai Y, Zhao J, Guo ZY, Wang MW. (2015) The insulinotrophic effect of insulin-like peptide 5 in vitro and in vivo. Biochem J, 466 (3): 467-73. [PMID:25514935]

56. 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 (1): 165-90. [PMID:17071007]

57. Ma S, Smith CM, Blasiak A, Gundlach AL. (2017) Distribution, physiology and pharmacology of relaxin-3/RXFP3 systems in brain. Br J Pharmacol, 174 (10): 1034-1048. [PMID:27774604]

58. Mallart S, Ingenito R, Bianchi E, Bresciani A, Esposito S, Gallo M, Magotti P, Monteagudo E, Orsatti L, Roversi D et al.. (2021) Identification of Potent and Long-Acting Single-Chain Peptide Mimetics of Human Relaxin-2 for Cardiovascular Diseases. J Med Chem, 64 (4): 2139-2150. [PMID:33555858]

59. Marwari S, Poulsen A, Shih N, Lakshminarayanan R, Kini RM, Johannes CW, Dymock BW, Dawe GS. (2019) Intranasal administration of a stapled relaxin-3 mimetic has anxiolytic- and antidepressant-like activity in rats. Br J Pharmacol, 176 (20): 3899-3923. [PMID:31220339]

60. 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 (1-2): 183-9. [PMID:10806363]

61. Muda M, He C, Martini PG, Ferraro T, Layfield S, Taylor D, Chevrier C, Schweickhardt R, Kelton C, Ryan PL et al.. (2005) Splice variants of the relaxin and INSL3 receptors reveal unanticipated molecular complexity. Mol Hum Reprod, 11 (8): 591-600. [PMID:16051677]

62. Nef S, Parada LF. (1999) Cryptorchidism in mice mutant for Insl3. Nat Genet, 22 (3): 295-9. [PMID:10391220]

63. Neschadim A, Pritzker LB, Pritzker KP, Branch DR, Summerlee AJ, Trachtenberg J, Silvertown JD. (2014) Relaxin receptor antagonist AT-001 synergizes with docetaxel in androgen-independent prostate xenografts. Endocr Relat Cancer, 21 (3): 459-71. [PMID:24812057]

64. Patil NA, Hughes RA, Rosengren KJ, Kocan M, Ang SY, Tailhades J, Separovic F, Summers RJ, Grosse J, Wade JD et al.. (2016) Engineering of a Novel Simplified Human Insulin-Like Peptide 5 Agonist. J Med Chem, 59 (5): 2118-25. [PMID:26824523]

65. Pustovit RV, Zhang X, Liew JJ, Praveen P, Liu M, Koo A, Oparija-Rogenmozere L, Ou Q, Kocan M, Nie S et al.. (2021) A Novel Antagonist Peptide Reveals a Physiological Role of Insulin-Like Peptide 5 in Control of Colorectal Function. ACS Pharmacol Transl Sci, 4 (5): 1665-1674. [PMID:34661082]

66. 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 (51): 20789-94. [PMID:24297931]

67. Rytova V, Ganella DE, Hawkes D, Bathgate RAD, Ma S, Gundlach AL. (2019) Chronic activation of the relaxin-3 receptor on GABA neurons in rat ventral hippocampus promotes anxiety and social avoidance. Hippocampus, 29 (10): 905-920. [PMID:30891856]

68. Scott DJ, Fu P, Shen PJ, Gundlach A, Layfield S, Riesewijk A, Tomiyama H, Hutson JM, Tregear GW, Bathgate RA. (2005) Characterization of the rat INSL3 receptor. Ann N Y Acad Sci, 1041: 13-6. [PMID:15956681]

69. 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]

70. 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]

71. Sedaghat K, Shen PJ, Finkelstein DI, Henderson JM, Gundlach AL. (2008) Leucine-rich repeat-containing G-protein-coupled receptor 8 in the rat brain: Enrichment in thalamic neurons and their efferent projections. Neuroscience, 156 (2): 319-33. [PMID:18706979]

72. Sethi A, Bruell S, Patil N, Hossain MA, Scott DJ, Petrie EJ, Bathgate RA, Gooley PR. (2016) The complex binding mode of the peptide hormone H2 relaxin to its receptor RXFP1. Nat Commun, 7: 11344. [PMID:27088579]

73. Shabanpoor F, Akhter Hossain M, Ryan PJ, Belgi A, Layfield S, Kocan M, Zhang S, Samuel CS, Gundlach AL, Bathgate RA et al.. (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 (4): 1671-81. [PMID:22257012]

74. Shabanpoor F, Bathgate RA, Belgi A, Chan LJ, Nair VB, Wade JD, Hossain MA. (2012) Site-specific conjugation of a lanthanide chelator and its effects on the chemical synthesis and receptor binding affinity of human relaxin-2 hormone. Biochem Biophys Res Commun, 420 (2): 253-6. [PMID:22425984]

75. Shabanpoor F, Bathgate RA, Hossain MA, Giannakis E, Wade JD, Hughes RA. (2007) Design, synthesis and pharmacological evaluation of cyclic mimetics of the insulin-like peptide 3 (INSL3) B-chain. J Pept Sci, 13 (2): 113-20. [PMID:17120268]

76. 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]

77. 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]

78. Shemesh R, Toporik A, Levine Z, Hecht I, Rotman G, Wool A, Dahary D, Gofer E, Kliger Y, Soffer MA et al.. (2008) Discovery and validation of novel peptide agonists for G-protein-coupled receptors. J Biol Chem, 283 (50): 34643-9. [PMID:18854305]

79. Smith CM, Hosken IT, Sutton SW, Lawrence AJ, Gundlach AL. (2012) Relaxin-3 null mutation mice display a circadian hypoactivity phenotype. Genes Brain Behav, 11 (1): 94-104. [PMID:21899720]

80. Smith CM, Shen PJ, Banerjee A, Bonaventure P, Ma S, Bathgate RA, Sutton SW, Gundlach AL. (2010) Distribution of relaxin-3 and RXFP3 within arousal, stress, affective, and cognitive circuits of mouse brain. J Comp Neurol, 518 (19): 4016-45. [PMID:20737598]

81. Sudo S, Kumagai J, Nishi S, Layfield S, Ferraro T, Bathgate RA, Hsueh AJ. (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 (10): 7855-62. [PMID:12506116]

82. 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]

83. 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]

84. Verdino P, Lee SL, Cooper FN, Cottle SR, Grealish PF, Hu CC, Meyer CM, Lin J, Copeland V, Porter G et al.. (2023) Development of a long-acting relaxin analogue, LY3540378, for treatment of chronic heart failure. Br J Pharmacol, 180 (15): 1965-1980. [PMID:36780899]

85. Walker AW, Smith CM, Chua BE, Krstew EV, Zhang C, Gundlach AL, Lawrence AJ. (2015) Relaxin-3 receptor (RXFP3) signalling mediates stress-related alcohol preference in mice. PLoS ONE, 10 (4): e0122504. [PMID:25849482]

86. Wang JH, Hu MJ, Zhang L, Shao XX, Lv CH, Liu YL, Xu ZG, Guo ZY. (2018) Exploring receptor selectivity of the chimeric relaxin family peptide R3/I5 by incorporating unnatural amino acids. Biochimie, 154: 77-85. [PMID:30102931]

87. Wang JH, Shao XX, Hu MJ, Wei D, Nie WH, Liu YL, Xu ZG, Guo ZY. (2017) Rapid preparation of bioluminescent tracers for relaxin family peptides using sortase-catalysed ligation. Amino Acids, 49 (9): 1611-1617. [PMID:28631012]

88. Wong LLL, Scott DJ, Hossain MA, Kaas Q, Rosengren KJ, Bathgate RAD. (2018) Distinct but overlapping binding sites of agonist and antagonist at the relaxin family peptide 3 (RXFP3) receptor. J Biol Chem, 293 (41): 15777-15789. [PMID:30131340]

89. Wu QP, Zhang L, Shao XX, Wang JH, Gao Y, Xu ZG, Liu YL, Guo ZY. (2016) Application of the novel bioluminescent ligand-receptor binding assay to relaxin-RXFP1 system for interaction studies. Amino Acids, 48 (4): 1099-1107. [PMID:26767372]

90. Xiao J, Huang Z, Chen CZ, Agoulnik IU, Southall N, Hu X, Jones RE, Ferrer M, Zheng W, Agoulnik AI et al.. (2013) Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1. Nat Commun, 4: 1953. [PMID:23764525]

91. Zhang C, Chua BE, Yang A, Shabanpoor F, Hossain MA, Wade JD, Rosengren KJ, Smith CM, Gundlach AL. (2015) Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice. Behav Brain Res, 292: 125-32. [PMID:26057358]

92. Zhang S, Hughes RA, Bathgate RA, Shabanpoor F, Hossain MA, Lin F, van Lierop B, Robinson AJ, Wade JD. (2010) Role of the intra-A-chain disulfide bond of insulin-like peptide 3 in binding and activation of its receptor, RXFP2. Peptides, 31 (9): 1730-6. [PMID:20570702]

93. 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 (1-3): 43-52. [PMID:18582868]

Subcommittee members: Roger J. Summers (Chairperson) Drug Discovery Biology Monash Institute of Pharmaceutical Sciences Monash University 399 Royal Parade Parkville,Victoria 3052 Australia Michelle Halls Drug Discovery Biology Monash Institute of Pharmaceutical Sciences Monash University 399 Royal Parade Parkville, Victoria 3052 AUSTRALIA Ross A.D. Bathgate Florey Institute of Neuroscience and Mental Health University of Melbourne Victoria 3010 AUSTRALIA Thomas Dschietzig Immundiagnostik AG Bensheim, Germany Charité-University Medicine Berlin Campus Mitte Medical Clinic for Cardiology and Angiology Berlin, Germany Relaxera Pharmazeutische Gesellschaft mbH & Co. KG, Bensheim, Germany Andrew L. Gundlach Florey Institute of Neuroscience and Mental Health The University of Melbourne Victoria 3010 Australia

Other contributors: Alexander I. Agoulnik Biomolecular Sciences Institute Florida International University Miami, FL USA Craig Smith Faculty of Health School of Medicine Deakin University Geelong Waurn Ponds Campus Waurn Ponds Australia