General

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 peptide receptor systems have roles in the cardiovascular system, modulate formation of connective tissue and bone, control aspects of reproduction, and act in the brain to regulate stress responses, anxiety and mood, arousal, spatial and social memory and motivated behaviors, including feeding and drug seeking. Relaxin has vasodilatory, anti-fibrotic, angiogenic, anti-apoptotic and anti-inflammatory properties. The effects of relaxin on tissue remodelling have 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. The potent renal [13] and cardiovascular [12] actions of relaxin lead to the first clinical trials in heart failure with relaxin. Phase II trials demonstrated positive renovascular effects and improvements in cardiovascular mortality at 60 and 180-days [56]. Phase IIIa trials demonstrated a significant reduction in mortality at day 180 [54] and importantly, plasma biomarkers of cardiac, renal, and hepatic damage and of decongestion were all significantly improved in serelaxin treated patients [38] consistent with relaxin preventing organ damage. While a subsequent Phase IIIb study did not meet long-term primary endpoints [39], serelaxin treated patients again demonstrated biomarker profiles consistent with positive renovascular effects and prevention of organ damage [55]. Importantly, metanalysis of all the serelaxin trial data suggests treatment of >5000 human patients with relaxin demonstrated no serious adverse effects while producing highly significant reductions in worsening heart failure and markers of renal function, but concluded that a 48 hr short-term treatment of AHF patients may not influence long-term outcomes [55]. Due to these promising results, and the considerable potential of relaxin as an anti-fibrotic, numerous pharmaceutical companies are developing chronic RXFP1 targeting therapies [15,53].

Relaxin was first identified in 1926 as a substance influencing the reproductive tract and was later demonstrated to be a peptide hormone with a two-chain structure similar to insulin. Subsequently several new members of this peptide family were identified, either by differential cloning (insulin-like peptide 3/4 (INSL3, INSL4) or by screening of the EST (INSL5, INSL6) and genomic (relaxin-3) databases. Relaxin-3 is a neuropeptide predominantly expressed in neurons of the nucleus incertus, which project widely to forebrain regions such as the hypothalamus, hippocampus and septum, and other limbic areas [34]. Rodent studies suggest that relaxin-3 has roles in arousal, feeding, stress responses, anxiety and addiction, and attention and memory [41]. The function and cognate receptors of the more recently evolved peptides, INSL4 and INSL6 are currently unknown.

The receptors for relaxin, relaxin-3, INSL3 and INSL5, RXFP1, RXFP2, RXFP3 and RXFP4 have all be cloned and sequenced. 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 activate tyrosine kinases [25]. 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 the glycoprotein hormones FSH, LH, and TSH and the R-spondins. 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 [42] and this is now known as RXFP2. The discovery that the orphan receptor LGR7 is the relaxin receptor, now RXFP1, was largely attributable to the pursuit of a hunch raised by the combination of the similarity of the structure of RXFP1 to RXFP2 and the similarity of the structure of relaxin to INSL3 [26]. RXFP1 and RXFP2, which in humans 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 [5]. Two additional orphan G protein-coupled receptors designated GPCR135 (RXFP3) and GPCR142 (RXFP4) were subsequently identified as receptors for relaxin-3 [31-32]. Unlike RXFP1 and RXFP2, RXFP3 and RXFP4 have short N-terminal extracellular domains, and contain only 469 and 374 amino acid residues, respectively. Cells transfected with RXFP3 [36] were used to identify relaxin-3 as a ligand in porcine brain extracts [32]. The other related receptor, RXFP4, also binds relaxin-3 [32], 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 [33]. Thus the relaxin family peptides, relaxin, INSL3, relaxin-3 and INSL5 have now been identified as the cognate ligands for the relaxin family peptide (RXFP) receptors 1-4 [4-5,22] (previously known as LGR7, LGR8, GPCR135 and GPCR142).

RXFP1 and RXFP2

RXFP1 has a widespread tissue distribution being found in female and male reproductive tissues, the brain and numerous other non-reproductive 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 in these tissues 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 [7]. 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 [5,35]. 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 [40,44-45]. 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. Interestingly, the effects of relaxin are also blocked by angiotensin AT₁ antagonists suggesting that RXFP1, AT₁ and AT₂ form complexes that may represent the functional correlate of these findings [10].

RXFP2 is expressed in rat ovary, testis and gubernaculum [7]. In the human, RXFP2 mRNA is found in the uterus and testis in Leydig cells, spermatocytes, spermatids and in the epididymal epithelium [2]. The identical cryptorchid phenotypes of the INSL3 and RXFP2 knockout mice demonstrated that INSL3/RXFP2 is essential for testis descent in rodents. There is less known about the role of INSL3/RXFP2 in adults, however there is evidence that INSL3/RXFP2 is involved in supporting germ cell function in the testis and ovary [28], probably interacting with RXFP2 receptors directly on the germ cells themselves [2]. More recently INSL3 has been shown to be a circulating hormone in women with levels correlating with the number of ovarian antral follicles [1,20] and elevated levels being associated with polycystic ovary syndrome [43]. Furthermore, 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 [19]. Deficits in INSL3/RXFP2 signaling are also correlated with reduced bone mass [16-17] and RXFP2 mutations may be linked with osteoporosis in men [18], suggesting that INSL3/RXFP2 has a role in bone physiology. RXFP2 is also present in a topographical distribution in the rat brain [50], associated with motor and limbic circuits.

RXFP1 and RXFP2 contain a large extracellular domain (ECD) with a leucine-rich repeat (LRR) domain and linker region connected to a low-density lipoprotein Class A (LDLa) module. The LDLa module is essential for the activation of both RXFP1 and RXFP2 by their ligands [48]. However, the mechanism by which relaxin and INSL3 bind and activate RXFP1 and RXFP2, respectively, are slightly different. INSL3 binding to the RXFP2 LRRs [49] mediates reorientation of the LDLa module by the linker region to activate the RXFP2 transmembrane domains in conjunction with the INSL3 A-chain [8]. In contrast, relaxin binds with high affinity to both the RXFP1 LRRs [9] and the linker [51] and this binding stabilizes a helical conformation of the linker that positions residues of the linker or LDLa + linker to bind the TMD and activate RXFP1 [23,30]. A small molecule RXFP1 agonist ML290 [57] that binds in the transmembrane domain and a relaxin peptidomimetic [24] that binds to the LRRs are biased agonists with distinct signalling profiles.

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 [11,14,37,46]. RXFP1 activation of adenylate cyclase is complex, involves interaction of the receptor with at least three G-proteins, Gα_s, Gα_oB and Gα_i3, and results in a biphasic pattern of cAMP accumulation [21,46-47]. 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 [21]).

RXFP3 and RXFP4

RXFP3 is predominantly expressed in the brain, whereas RXFP4 is present in brain, kidney, testis, thymus, placenta, prostate, salivary gland, thyroid and colon [7,32]. RXFP3 is present in many areas of the brain, in specific nuclei and neuron types, including in the olfactory bulb, cerebral cortex, septum, hippocampus, amygdala, hypothalamus, thalamus, midbrain, and brainstem [33]. Recent neurophysiological studies of hypothalamic oxytocin- and arginine-vasopressin-synthesizing magnocellular neurosecretory neurons indicate that RXFP3 activation inhibits these cells in male and female rats, and that this inhibition depends on an M-like potassium conductance [27].

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 [6,52]. Relaxin-3 is the cognate ligand for RXFP3, but it can also activate RXFP4 [31-32]; although this interaction is unlikely to have physiological significance because of a mismatch of sites of synthesis, storage and release. The receptors differ structurally and functionally from RXFP1 and RXFP2. They have relatively short N-terminal extracellular domains, and couple predominantly to Gα_i/o. Studies with native relaxin-3 purified from brain extracts and recombinant human relaxin-3 indicated that this peptide potently stimulates GTPγS binding and inhibits cAMP accumulation in cells expressing RXFP3 or 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 RXFP4 [33]. Studies of RXFP3 signalling reveal that in addition to inhibition of cAMP production, RXFP3 also activates p38MAPK, JNK1/2 and ERK1/2 when activated by relaxin-3 and that relaxin causes biased signaling [29]. 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 G_i/o proteins and the receptor interacts with GRK2, β-arrestins and readily internalizes [3].

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