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The relaxin family peptide (RXFP) receptors are a group of 4 receptors, that mediate the hormonal and neuropeptide actions of the relaxin family peptides relaxin (human gene 2 relaxin or other mammalian equivalents), insulin-like peptide (INSL) 3, relaxin-3 and INSL5 (Table 1). These receptor systems have roles in the cardiovascular system, modulate formation of connective tissue and bone, control aspects of reproduction, act in the brain as neuropeptides to regulate stress responses, anxiety and mood, arousal, and motivated behaviors including feeding and drug seeking. The effects of relaxin on tissue remodelling has the potential for far-reaching therapeutic consequences since fibrosis is a hallmark of all forms of progressive cardiovascular and renal disease and obstructive airway disease (asthma), which collectively contribute to 40-50% of deaths in developed countries. Relaxin is in advanced clinical trials for the treatment of acute heart failure (defined as new-onset or, more frequently, worsening of known heart failure). In the Pre-RELAX (phase II) and RELAX (phase III) trials [49-50], relaxin moderately improved dyspnoea (the primary endpoint), was exceptionally safe, improved renal function, and lowered all-cause as well as cardiovascular mortality at day 180.
The phase-III trial RELAX-AHF tested recombinant human relaxin-2 (rhRlx) in Acute Heart Failure (AHF) and found it to improve clinical symptoms moderately (primary endpoint), to be neutral regarding death and hospitalization at day 60 (secondary endpoint), to be safe, and to lower mortality at day 180 (improvement from 9.6 to 6.1 % for cardio-vascular and from 11.3 to 7.3 % for all-cause mortality) . As this trial was not designed as mortality trial a second phase III mortality study, RELAX-AHF-2, is currently being conducted with results being anticipated in late 2017/early 2018.
A post hoc analysis of RELAX  illustrated remarkable and clinically relevant organ-protective effects of relaxin treatment: The changes of several biomarkers; such as troponin T, cystatin C, liver transaminases, and NT-proBNP; during the first 48 hours of treatment were highly predictive for mortality at day 180. Those markers reflect heart, kidney, and liver damage as well as decongestion; and all of them have been reported in earlier studies to be associated with 180-day all-cause mortality in AHF [15,29,36]. Recombinant human relaxin (rhRlx), in turn, beneficially affected all of these parameters: In the rhRlx group, only 16 % cf 27 % in the placebo group experienced a troponin increase by ≥20 % at day 2; only 16 % vs 23 % a cystatin C rise ≥0.3 mg/l, and only 7 % vs 13 % an AST elevation ≥20 %. In contrast, 69 % vs 58 % had a decline of NT-proBNP ≥30 % within 48 hours indicating decongestion.
Relaxin was first identified in 1926 as a substance influencing the reproductive tract and was subsequently found to be a peptide hormone with a two-chain structure similar to insulin. In more recent years several new members of this peptide family have been identified, either by differential cloning (insulin-like peptide 3 (INSL3), INSL4) or by screening of the EST (INSL5, INSL6) and genomic (relaxin-3) databases. Although these peptides have been termed 'insulin-like', phylogenetic analyses indicates that they evolved from a relaxin-3 ancestral gene prior to the emergence of fish [51-52]. Relaxin-3 and INSL5, are highly expressed in the brain and gastrointestinal tract, respectively, and likely have highly conserved, but as yet not fully understood, functions. In contrast, there has been a rapid expansion of this family in mammals with the emergence of INSL3, INSL4 and INSL6. The term "neohormones" has been coined to describe such hormone systems specific to mammalian physiology, often addressing post-reproductive mammalian traits, and likely to represent important pharmacological targets in the clinical management of aging .
The receptors for relaxin, relaxin-3, INSL3 and INSL5 were identified recently. Based on the hypothesized coevolution of peptide ligands and their receptors, there was a school of thought that believed the receptors for relaxin and INSL3 were likely to be related to the known insulin receptors and as such be tyrosine kinases. However there was also clear evidence that relaxin caused increases in cAMP in reproductive tissues and cell lines. It is now known that, in spite of their structural similarity, relaxin and insulin family peptides act through independent signalling pathways: the relaxin group activate GPCRs, whereas the insulin group activates tyrosine kinases . Relaxin and INSL3 receptors are a subgroup (type C) of the family of leucine-rich repeat-containing guanine nucleotide binding (G protein)-coupled receptors or LGRs, that include the receptors for FSH, LH, and TSH. By using inferences from similar phenotypic expression following mutation and inactivation of INSL3 and a transgenic insertional mutation in mouse chromosome 5, an orphan LGR designated either Great (G protein-coupled receptor affecting testis descent) or LGR8 was postulated to be the INSL3 receptor . The discovery that the orphan receptor LGR7 is the relaxin receptor was largely attributable to the pursuit of a hunch raised by the combination of the similarity of the structure of LGR7 to LGR8 and the similarity of the structure of relaxin to INSL3 . LGR7 and LGR8, which are 757 and 737 amino acids in length, respectively, share about 60% amino acid sequence identity and contain 10 leucine-rich repeats in their large N-terminal extracellular domain . Two additional orphan G protein-coupled receptors designated GPCR135 and GPCR142 were more recently identified as receptors for relaxin-3 [30-31]. Unlike LGR7 and LGR8, GPCR135 and GPCR142 have short N-terminal extracellular domains, and they contain only 469 and 374 amino acid residues, respectively. Cells transfected with GPCR135 (also known as Somatostatin and Angiotensin-Like Peptide Receptor, SALPR)  were used to identify relaxin-3 as a ligand in porcine brain extracts . The other related receptor, GPCR142, also binds relaxin-3 , but on the basis of more recent evidence based on co-localisation of receptor and its cognate ligand it is now clear that it is the receptor for INSL5 . Thus the relaxin family peptides, relaxin, INSL3, relaxin-3 and INSL5 have now been identified as the cognate ligands for LGR7, LGR8, GPCR135 and GPCR142 now known as relaxin family peptide (RXFP) receptors 1-4 [4-5,21].
The RXFPs have a widespread tissue distribution. RXFP1 is found in female and male reproductive tissues, the brain and numerous other nonreproductive tissues such as the kidney, heart and lung. Female reproductive tissues that respond to relaxin include: pubic symphysis, cervix, uterus, nipples and mammary glands, although the relative importance of the functions varies with species. Relaxin is also produced in the male reproductive tract, is present in semen and has been suggested to increase sperm motility and penetration into oocytes . There is increasing evidence that relaxin has important roles in the cardiovascular adaptive changes associated with pregnancy. These include increases in plasma volume, cardiac output and heart rate, together with decreased blood pressure and vascular resistance. In brain, RXFP1 is localised to discrete regions of the olfactory system, neocortex, hypothalamus, hippocampus, thalamus, amygdala, midbrain, and medulla of the male and female rat [5,33]. In addition to the specific roles of relaxin already described, it has more general physiological roles. Relaxin inhibits collagen biosynthesis and promotes collagen breakdown in reproductive tissues but also has similar effects in non-reproductive tissues, which has led to the suggestion that relaxin would be an effective treatment for fibrotic diseases [37,40-41]. It was recently discovered that the anti-fibrotic actions of relaxin are dependent on the presence of the angiotensin AT2 receptor, can be blocked by AT2 antagonists and are not observed in AT2 knockout mice. RXFP1 and AT2 also form heterodimers that may represent the functional correlate of these findings .
RXFP2 is expressed in rat ovary, testis and gubernaculum . In the human, RXFP2 mRNA is found in the uterus and testis in Leydig cells, spermatocytes, spermatids and in the epididymal epithelium . The identical cryptorchid phenotypes of the INSL3 and RXFP2 knockout mice demonstrated that INSL3/RXFP2 in essential for testis descent in rodents. There is less known about the role of INSL3/RXFP2 in adults, however there is evidence that Recent studies indicate that INSL3/RXFP2 is involved in supporting germ cell function in the testis and ovary , probably interacting with RXFP2 receptors directly on the germ cells themselves . More recently INSL3 has been shown to be a circulating hormone in women with levels correlating with the number of ovarian antral follicles [1,18] and elevated levels being associated with polycystic ovary syndrome . Furthermore, Importantly, a recent study in cows demonstrated that RXFP2 is expressed on thecal cells and INSL3 has a positive autoregulatory role in maintaining thecal androgen production that is essential for normal ovarian follicle development . Deficits in INSL3/RXFP2 signaling are also correlated with reduced bone mass [12-13] and RXFP2 mutations may be linked with osteoporosis in men , suggesting that INSL3/RXFP2 has a role in bone physiology. RXFP2 is also present is a topographical distribution in the rat brain , associated with motor and limbic circuits.
RXFP1 and RXFP2 possess complex binding characteristics and interaction with the cognate peptides involves interaction with multiple receptor domains. Hence the ligands bind with high affinity to the extracellular domain and a putatively lower affinity site in at least three stages. High-affinity binding initially occurs between the B-chain of relaxin and the RXFP1 leucine rich repeat region, with lower affinity binding to the transmembrane extracellular loops [10,22,48]. However ligand binding alone does not induce signalling and it is the N-terminal LDLa module which is essential for activation and acts as a tethered agonist interacting with the transmembrane domain to induce signalling [19,44,46,48]. RXFP1 can also be activated by the allosteric agonist ML290 that binds to an allosteric site involving interactions with TM7 and produces its effects by interacting with the third extracellular loop of human RXFP1 . RXFP1 activates adenylyl cyclase, guanylyl cyclase, PKA, PKC, PI-3-kinase, p38MAPK and ERK1/2 and also interacts with the glucocorticoid receptor. Longer term exposure of RXFP1 to relaxin causes changes in the expression of a number of genes including nNOS, VEGF, ETB receptor, MMP-2 and MMP-9 [9,11,35,42]. RXFP1 activation of adenylate cyclase is complex, involves interaction of the receptor with at least three G-proteins, Gαs, GαoB and Gαi3, and results in a biphasic pattern of cAMP accumulation [20,42-43]. RXFP2 activates adenylate cyclase in recombinant systems but some physiological responses are sensitive to pertussis toxin. It is now becoming clear that the interaction of RXFP2 with adenylate cyclase involves a subset of G proteins utilised by RXFP1 and that the differences may explain the different patterns of cAMP accumulation observed in vivo ).
RXFP3 is predominantly expressed in the brain whereas RXFP4 is found in brain, kidney, testis, thymus, placenta, prostate, salivary gland, thyroid and colon [7,31]. RXFP3 is found in many areas of the brain including hypothalamus, supraoptic nucleus, periaqueductal gray, nucleus incertus, brainstem, olfactory bulb, sensory cortex, amygdala, thalamus, paraventricular nucleus, inferior and superior colliculus .
In contrast to the high affinity interactions between relaxin and RXFP1, and INSL3 and RXFP2, relaxin-3 has a lower affinity for RXFP1 than relaxin [6,48]. Relaxin-3 is the known cognate ligand for RXFP3 but it can also activate RXFP4 [30-31] although this interaction is unlikely to have physiological significance. The receptors differ structurally and functionally from RXFP1 and RXFP2. They have relatively short N-terminal extracellular domains, and couple predominantly to Gαi/o. Studies with native relaxin-3 purified from brain extracts and recombinant human relaxin-3 indicated that this hormone potently stimulates GTPγS binding and inhibits cAMP accumulation in cells expressing RXFP3 and RXFP4. Based on the patterns of expression of ligand and receptor, relaxin-3 is recognised as the cognate ligand for RXFP3 and INSL5 is the cognate ligand for RFXP4 . Recent studies of RXFP3 signalling show that in addition to inhibition of cAMP production, RXFP3 also activates p38MAPK, JNK1/2 and ERK1/2 when treated with relaxin-3 and that relaxin causes biased signaling . RXFP4 when activated by INSL5 not only inhibits cAMP production but also causes phosphorylation of ERK1/2, p38MAPK, Akt and S6 ribosomal protein. Signalling is mediated principally through Gi/o proteins and the receptor interacts with GRK2, β-arrestins and readily internalizes . INSL5 is synthesized and secreted from L cells in the colon/rectum and there is evidence that it has roles in control of food intake and glucose homeostasis .
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To cite this family introduction, please use the following:
Roger Summers, Michelle Halls, Thomas Dschietzig, Ross Bathgate, Andrew L. Gundlach.
Relaxin family peptide receptors, introduction. Last modified on 15/09/2016. Accessed on 24/04/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=60.