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

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

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* 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]

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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