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Gene and Protein Information  |
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| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 757 | 4q32.1 | RXFP1 | relaxin family peptide receptor 1 | 74 |
| Mouse | 7 | 758 | 3 E3 | Rxfp1 | relaxin/insulin-like family peptide receptor 1 | 126 |
| Rat | 7 | 758 | 2q33 | Rxfp1 | relaxin family peptide receptor 1 | 126 |
| Previous and Unofficial Names |
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| LGR7 [73-74] | RXFPR1 | relaxin receptor 1 | leucine-rich repeat-containing G-protein-coupled receptor 7 [73-74] | RX1 | relaxin/insulin like family peptide receptor 1 | |
| Database Links |
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| Specialist databases | |
| GPCRdb | rxfp1_human (Hs), rxfp1_mouse (Mm), rxfp1_rat (Rn) |
| Other databases | |
| Alphafold | Q9HBX9 (Hs), Q6R6I7 (Mm), Q6R6I6 (Rn) |
| CATH/Gene3D | 3.80.10.10 |
| ChEMBL Target | CHEMBL1293316 (Hs), CHEMBL3714701 (Mm), CHEMBL4739859 (Rn) |
| Ensembl Gene | ENSG00000171509 (Hs), ENSMUSG00000034009 (Mm), ENSRNOG00000024120 (Rn) |
| Entrez Gene | 59350 (Hs), 381489 (Mm), 295144 (Rn) |
| Human Protein Atlas | ENSG00000171509 (Hs) |
| KEGG Gene | hsa:59350 (Hs), mmu:381489 (Mm), rno:295144 (Rn) |
| OMIM | 606654 (Hs) |
| Pharos | Q9HBX9 (Hs) |
| RefSeq Nucleotide | NM_021634 (Hs), NM_212452 (Mm), NM_201417 (Rn) |
| RefSeq Protein | NP_067647 (Hs), NP_997617 (Mm), NP_958820 (Rn) |
| UniProtKB | Q9HBX9 (Hs), Q6R6I7 (Mm), Q6R6I6 (Rn) |
| Wikipedia | RXFP1 (Hs) |
| Natural/Endogenous Ligands |
| relaxin-1 {Sp: Human} |
| relaxin {Sp: Human} |
| relaxin-3 {Sp: Human} |
| Comments: Relaxin is the most potent endogenous agonist and is the cognate ligand for RXFP1. There is cross reactivity between relaxin family peptides and their receptors: relaxin binds to and activates RXFP1 and RXFP2 and is a biased agonist at RXFP3; relaxin-3 binds to and activates RXFP1, RXFP3 and RXFP4. |
| Potency order of endogenous ligands (Human) |
| relaxin (RLN2, P04090) = relaxin-1 (RLN1, P04808) > relaxin-3 (RLN3, Q8WXF3) [135] |
Download all structure-activity data for this target as a CSV file 
| Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| View species-specific agonist tables | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Human relaxin and porcine relaxin activate RXFP1 and RXFP2 and are biased agonists at RXFP3 (untested at RXFP4). Rat relaxin selectively activates RXFP1 not RXFP2 (untested at RXFP3 and RXFP4). Human relaxin-3 activates RXFP1 but not RXFP2, is the cognate ligand for RXFP3 and also activates RXFP4. Rhesus monkey relaxin activates RXFP1 and RXFP2 (untested at RXFP3 and RXFP4). Affinity values were determined in HEK 293 cells expressing human RXFP1. Compounds 54, 59 and 64 are long-acting single-chain (B-chain) relaxin peptide mimetics. Testing of these peptides was cAMP accumulation in OVCAR5 cells expressing endogenous RXFP1 [100]. A(4-24)(B7-24)H2 is a synthetic peptide comprising the minimal active core of relaxin, with improved selectivity over RXFP2. A(4-24)(F23A)H2 has a minimised A-chain including an F23A mutation, generating improved selectivity for RXFP1 over RXFP2. A single chain derivative of relaxin, B7-33 is a functionally selective agonist at RXFP1 that preferentially activates ERK1/2 over cAMP. B7-33 has anti-fibrotic properties like relaxin but unlike relaxin does not promote tumour growth in vivo [67]. Short linear peptides derived from a naturally occurring protein containing a collagen-like repeat, have been reported to act at RXFP1 [132]. Although the effects produced by the peptides CGEN-25009 and CGEN-25010 in several systems were extremely variable and the effects of human relaxin in these systems unusual [132], there is some evidence to suggest relaxin-like activity of these peptides in THP-1 cells and in a fibrosis model [119]. In the latter study, CGEN-25009 and human relaxin increased cAMP, cGMP and nitrite, decreased collagen deposition and increased MMP2 activity in human dermal fibroblasts [119]. More recent studies with these peptides and the precursor protein C1q-tumor necrosis factor-related protein 8 (CTRP8) demonstrated activation of RXFP1 [55] with cAMP production and a PI3K mediated pro-migratory phenotype in glioblastoma cell lines and primary cells. Co-immunoprecipitation studies demonstrated a direct interaction between human CTRP8 and RXFP1. Although these studies suggest that CTRP8 or peptide fragments are able to activate RXFP1, it remains to be seen whether they are native ligands. |
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| Antagonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Antagonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| RXFP1-truncate is a naturally occurring splice variant of the receptor that includes the LDLa region that acts as a functional antagonist of RXFP1 [127]. It has been identified in mouse, rat and pig, and in rodents levels rise in late pregnancy suggesting that it may have a physiological role in antagonising the actions of relaxin. B-R13/17K H2 is also referred to as AT-001, and has mutations R13K and R17K within the relaxin binding motif. B-R13/17K H2 is a partial agonist in recombinant systems with high RXFP1 expression and an antagonist in physiological systems with lower receptor expression. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Allosteric Modulators | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| ML290 is the first small molecule activator of RXFP1. The actions of ML290 are species-specific being active at the human RXFP1 with no agonist action at the mouse receptor. ML290 is a biased allosteric agonist at RXFP1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
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Gs family Gi/Go family |
Adenylyl cyclase stimulation Adenylyl cyclase inhibition |
| Comments: RXFP1 displays complex cAMP signalling. RXFP1 couples to Gs to increase cAMP, an effect that is negatively modulated by coupling to GoB. RXFP1 also couples to Gi3 to activate a delayed surge of cAMP accumulation via a Gβγ-PI3K-PKCζ pathway that activates AC5. cAMP accumulation may also occur in response to relaxin by a G protein-independent mechanism, and in some cells may be downstream of tyrosine kinase inhibition of phosphodiesterase activity. A constitutive RXFP1-dependent cAMP response occurs in single rat cardiac fibroblasts, HeLa cells, and HEK293 cells expressing RXFP1. The response is dependent upon a protein complex, or signalosome, linked to the relaxin receptor, and the signalosome is highly sensitive to attomolar concentrations of relaxin. | |
| References: 4,9,58-59,61-62,64,73-74,94,110-112 | |
| Secondary Transduction Mechanisms |
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| Transducer | Effector/Response |
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Gs family Gi/Go family |
Guanylate cyclase stimulation Other - See Comments |
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Comments:
Responses also include kinase activation and other signalling pathways. Guanylate cyclase stimulation occurs secondary to increased NOS activity. Depending on the cell type under investigation, relaxin may activate endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS) or stimulate the expression of inducible NOS (iNOS). In rat isolated lungs, the relaxin-mediated iNOS upregulation depends on a subtle balance between stimulatory ERK1/2 activation and counter-regulatory PI3K stimulation. When stimulated by relaxin, RXFP1 activates a number of MAP kinases (including MEK, ERK1/2, Akt and p38), depending on the cell type in question. Activation of ERK1/2 is dependent on G protein coupling in rat renal myofibroblasts. The allosteric agonist ML-290 stimulates many of the pathways activated by relaxin but does not cause ERK1/2 activation. Activation of PI3K and NOS-NO-cGMP signalling pathways by RXFP1 leads to inhibition of TGF-β1 signalling, and this is responsible for the anti-fibrotic effects of relaxin. Relaxin activates the glucocorticoid receptor, a nuclear receptor that acts as a ligand-dependent transcription factor. The activation, and the subsequent changes in gene transcription, may account for the many effects of relaxin upon the expression levels of a variety of proteins, including those involved in connective tissue metabolism. |
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| References: 2-3,5,7-8,24,40-43,107,113,125,155 | |
| Tissue Distribution
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| Expression Datasets |
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| Functional Assays
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| Physiological Functions
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| Physiological Consequences of Altering Gene Expression
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| Phenotypes, Alleles and Disease Models
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| Biologically Significant Variants
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| General Comments |
| Many studies have examined RXFP1 tissue expression using a range of techniques. Most provide complimentary data but RT-PCR studies are subject to the usual caveats regarding the extent of amplification of physiologically relevant copy numbers of mRNA. Receptor autoradiography has also been used to provide quantitative data on properties of RXFP1 in particular tissue locations which is in good agreement with other methods. |
1. Adams J, Schott S, Bern A, Renz M, Ikenberg K, Garbe C, Busch C. (2012) A novel role for relaxin-2 in the pathogenesis of primary varicosis. PLoS One, 7 (6): e39021. [PMID:22737225]
2. Ahmad N, Wang W, Nair R, Kapila S. (2012) Relaxin induces matrix-metalloproteinases-9 and -13 via RXFP1: induction of MMP-9 involves the PI3K, ERK, Akt and PKC-ζ pathways. Mol Cell Endocrinol, 363 (1-2): 46-61. [PMID:22835547]
3. Alexiou K, Wilbring M, Matschke K, Dschietzig T. (2013) Relaxin protects rat lungs from ischemia-reperfusion injury via inducible NO synthase: role of ERK-1/2, PI3K, and forkhead transcription factor FKHRL1. PLoS ONE, 8 (9): e75592. [PMID:24098703]
4. Anand-Ivell R, Heng K, Bartsch O, Ivell R. (2007) Relaxin signalling in THP-1 cells uses a novel phosphotyrosine-dependent pathway. Mol Cell Endocrinol, 272 (1-2): 1-13. [PMID:17509748]
5. Baccari MC, Bani D, Bigazzi M, Calamai F. (2004) Influence of relaxin on the neurally induced relaxant responses of the mouse gastric fundus. Biol Reprod, 71 (4): 1325-9. [PMID:15215200]
6. Baccari MC, Nistri S, Quattrone S, Bigazzi M, Bani Sacchi T, Calamai F, Bani D. (2004) Depression by relaxin of neurally induced contractile responses in the mouse gastric fundus. Biol Reprod, 70 (1): 222-8. [PMID:14522837]
7. Baccari MC, Nistri S, Vannucchi MG, Calamai F, Bani D. (2007) Reversal by relaxin of altered ileal spontaneous contractions in dystrophic (mdx) mice through a nitric oxide-mediated mechanism. Am J Physiol Regul Integr Comp Physiol, 293 (2): R662-8. [PMID:17522128]
8. Bani D, Failli P, Bello MG, Thiemermann C, Bani Sacchi T, Bigazzi M, Masini E. (1998) Relaxin activates the L-arginine-nitric oxide pathway in vascular smooth muscle cells in culture. Hypertension, 31 (6): 1240-7. [PMID:9622136]
9. Bartsch O, Bartlick B, Ivell R. (2001) Relaxin signalling links tyrosine phosphorylation to phosphodiesterase and adenylyl cyclase activity. Mol Hum Reprod, 7 (9): 799-809. [PMID:11517286]
10. Bartsch O, Bartlick B, Ivell R. (2004) Phosphodiesterase 4 inhibition synergizes with relaxin signaling to promote decidualization of human endometrial stromal cells. J Clin Endocrinol Metab, 89 (1): 324-34. [PMID:14715868]
11. 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]
12. Bathgate RA, Lin F, Hanson NF, Otvos L, Guidolin A, Giannakis C, Bastiras S, Layfield SL, Ferraro T, Ma S, Zhao C, Gundlach AL, Samuel CS, Tregear GW, Wade JD. (2006) Relaxin-3: Improved Synthesis Strategy and Demonstration of Its High-Affinity Interaction with the Relaxin Receptor LGR7 Both In Vitro and In Vivo. Biochemistry, 45: 1043-1053. [PMID:16411781]
13. Bathgate RAD, Hsueh AJW, Sherwood OD. (2005) Physiology and molecular biology of the relaxin peptide family. In Physiology of Reproduction. Edited by Knobil E, Neill JD (Elsevier) 679-968. [ISBN:0125154003]
14. Bezhaeva T, de Vries MR, Geelhoed WJ, van der Veer EP, Versteeg S, van Alem CMA, Voorzaat BM, Eijkelkamp N, van der Bogt KE, Agoulnik AI et al.. (2018) Relaxin receptor deficiency promotes vascular inflammation and impairs outward remodeling in arteriovenous fistulas. FASEB J,: fj201800437R [Epub ahead of print]. [PMID:29882709]
15. Bigazzi M, Brandi ML, Bani G, Sacchi TB. (1992) Relaxin influences the growth of MCF-7 breast cancer cells. Mitogenic and antimitogenic action depends on peptide concentration. Cancer, 70 (3): 639-43. [PMID:1320450]
16. Boccalini G, Sassoli C, Bani D, Nistri S. (2018) Relaxin induces up-regulation of ADAM10 metalloprotease in RXFP1-expressing cells by PI3K/AKT signaling. Mol Cell Endocrinol, 472: 80-86. [PMID:29180109]
17. Bond CP, Parry LJ, Samuel CS, Gehring HM, Lederman FL, Rogers PA, Summers RJ. (2004) Increased expression of the relaxin receptor (LGR7) in human endometrium during the secretory phase of the menstrual cycle. J Clin Endocrinol Metab, 89 (7): 3477-85. [PMID:15240635]
18. Braddon SA. (1978) Relaxin-dependent adenosine 6',5'-monophosphate concentration changes in the mouse pubic symphysis. Endocrinology, 102 (4): 1292-9. [PMID:217619]
19. Cardoso LC, Nascimento AR, Royer C, Porto CS, Lazari MF. (2010) Locally produced relaxin may affect testis and vas deferens function in rats. Reproduction, 139 (1): 185-96. [PMID:19812235]
20. Carvalho LN, Cristovam PC, Passos CS, Boim MA. (2012) Mesangial cells cultured from pregnant rats display reduced reactivity to angiotensin II: the role of relaxin, nitric oxide and AT2 receptor. Cell Physiol Biochem, 30 (6): 1456-64. [PMID:23207895]
21. Chan LJ, Rosengren KJ, Layfield SL, Bathgate RA, Separovic F, Samuel CS, Hossain MA, Wade JD. (2012) Identification of key residues essential for the structural fold and receptor selectivity within the A-chain of human gene-2 (H2) relaxin. J Biol Chem, 287 (49): 41152-64. [PMID:23024363]
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