Relaxin family peptide receptors (RXFP, nomenclature as agreed by the NC-IUPHAR Subcommittee on Relaxin family peptide receptors [2,12]) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are a number of 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 – relaxin (RLN2, P04090) interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [34] and porcine relaxin may have a higher efficacy than human relaxin (RLN2, P04090) [13]. Relaxin-3 (RLN3, Q8WXF3) has differential affinity for RXFP2 between species; mouse and rat RXFP2 have a higher affinity for relaxin-3 (RLN3, Q8WXF3) [33]. At least two binding sites have been identified on RXFP1 and RXFP2: 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 domain [13,43]. The unique N-terminal LDLa module of RXFP1 and RXFP2 is essential for receptor signalling [35].

Relaxin is the cognate peptide ligand for RXFP1 and is in extended Phase III clinical trials for the treatment of acute heart failure [29]. Relaxin has vasodilatory, anti-fibrotic, angiogenic, anti-apoptotic and anti-inflammatory effects. Small molecule allosteric agonists such as ML290 have been developed [41,48]. The antifibrotic actions of relaxin are dependent on the angiotensin receptor AT₂ [5]. RXFP2 and its cognate ligand INSL3 have a more specialized role with mutations reported in patients with cryptorchidism [7]. cAMP elevation is the major signalling pathway for RXFP1 and RXFP2 [21-22], but RXFP1 also activates MAP kinases, nitric oxide signalling, tyrosine kinase phosphorylation and relaxin can interact with glucocorticoid receptors [15]. RXFP1 signalling involves lipid rafts, residues in the C-terminus of the receptor and activation of phosphatidylinositol-3-kinase [16] and pre-assembled protein complexes [14]. Receptor expression profiles suggest that RXFP3 is a brain neuropeptide receptor and RXFP4 a gut hormone receptor with the relaxin-3/RXFP3 system modulating feeding [8-9,17,36,42], anxiety [32,49], and reward and motivated goal-directed behaviours [18,32,46]. 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. Unlike RXFP1 and RXFP2, both RXFP3 and RXFP4 are encoded by a single exon. INSL5 is secreted from enteroendocrine L cells and the INSL5/RXFP4 system controls food intake and glucose homeostasis [10]. RXFP3 and RXFP4 couple to G_i/o and inhibit adenylyl cyclase [27,44], and also cause Erk1/2 phosphorylation [44]. RXFP4 also causes phosphorylation of p38MAPK, Akt and S6RP [1]. There is evidence that at RXFP3, relaxin (RLN2, P04090) is a biased ligand compared to the cognate ligand relaxin-3.

* 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: 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]

* 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]

* 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]

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Subcommittee members: Roger 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 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