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Gene and Protein Information | ||||||
class A G protein-coupled receptor | ||||||
Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | 7 | 469 | 5p13.2 | RXFP3 | relaxin family peptide receptor 3 | 53 |
Mouse | 7 | 472 | 15 A1 | Rxfp3 | relaxin family peptide receptor 3 | 70 |
Rat | 7 | 476 | 2q16 | Rxfp3 | relaxin family peptide receptor 3 |
Previous and Unofficial Names |
RLN3R1 | RXFPR3 | GPCR135 | relaxin/insulin like family peptide receptor 3 |
Database Links | |
Specialist databases | |
GPCRdb | rl3r1_human (Hs), rl3r1_mouse (Mm), q5y986_rat (Rn) |
Other databases | |
Alphafold | Q9NSD7 (Hs), Q8BGE9 (Mm), Q5Y986 (Rn) |
ChEMBL Target | CHEMBL1628472 (Hs) |
Ensembl Gene | ENSG00000182631 (Hs), ENSMUSG00000060735 (Mm), ENSRNOG00000023126 (Rn) |
Entrez Gene | 51289 (Hs), 239336 (Mm), 294807 (Rn) |
Human Protein Atlas | ENSG00000182631 (Hs) |
KEGG Gene | hsa:51289 (Hs), mmu:239336 (Mm), rno:294807 (Rn) |
OMIM | 609445 (Hs) |
Pharos | Q9NSD7 (Hs) |
RefSeq Nucleotide | NM_016568 (Hs), NM_178717 (Mm), NM_001008310 (Rn) |
RefSeq Protein | NP_057652 (Hs), NP_848832 (Mm), NP_001008311 (Rn) |
UniProtKB | Q9NSD7 (Hs), Q8BGE9 (Mm), Q5Y986 (Rn) |
Wikipedia | RXFP3 (Hs) |
Natural/Endogenous Ligands |
INSL5 {Sp: Human} |
relaxin-3 {Sp: Human} |
relaxin {Sp: Human} |
relaxin-3 (B chain) {Sp: Human} |
Comments: Relaxin-3 is a potent endogenous agonist for RXFP3. Unlike other relaxins, the relaxin-3 (B) chain has some bioactivity. Relaxin is a biased agonist at RXFP3. Neither relaxin-3 (B) chain or relaxin are known to act on RXFP3 in vivo. |
Potency order of endogenous ligands (Human) |
relaxin-3 (RLN3, Q8WXF3) > relaxin-3 (B chain) (RLN3, Q8WXF3) > relaxin (RLN2, P04090) [46] |
Download all structure-activity data for this target as a CSV file
Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Relaxin-3 activates RXFP3 but also RXFP4 and RXFP1. Relaxin-3 is highly conserved across species and is believed to be the ancestral relaxin. Affinity and pEC50 values were obtained in COS-7 cells transiently expressing RXFP3 or CHO or HEK293 cells stably expressing RXFP3. Relaxin is a biased agonist at RXFP3, compared to relaxin-3. Europium R3/I5 is used as a labelled ligand as an alternative to 125I labelled ligands in binding studies. The 'HC' in H3 Ac-B10-27(13-17HC)= hydrocarbon staple. |
Antagonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Antagonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Affinity values were determined in COS-7 cells transiently expressing or CHO or HEK293 cells stably expressing human RXFP3 labelled using [125I]relaxin-3, [125I]R3/I5 or europium-R3/I5. Antagonists produce rightward shifts of the concentration-response curve to relaxin-3 induced inhibition of forskolin stimulated cAMP accumulation in SK-N-MC cells expressing human RXFP3. R3(BΔ23-27)R/I5 also acts as a partial agonist or biased agonist in some systems [36]. Europium labelled R3(B1-22R) is used as an alternative to radiolabelled ligands. |
Allosteric Modulators | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Allosteric Modulator Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||
135PAM1 only allosterically modulates responses to the amidated form of relaxin-3 not the native form. |
Primary Transduction Mechanisms | |
Transducer | Effector/Response |
Gi/Go family | Other - See Comments |
Comments: In addition to adenylyl cyclase inhibition, activation of RXFP3 also causes GTPγS binding, ERK1/2 and p38MAP kinase phosphorylation. In CHO cells Gi2 is the major G protein involved but in HEK293 cells Gi3 GOB and GOA are all involved suggesting that cellular context is important in determining the response observed. | |
References: 5,13,45-47 |
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Clinically-Relevant Mutations and Pathophysiology | ||||||||
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2. Albert-Gascó H, Ma S, Ros-Bernal F, Sánchez-Pérez AM, Gundlach AL, Olucha-Bordonau FE. (2017) GABAergic Neurons in the Rat Medial Septal Complex Express Relaxin-3 Receptor (RXFP3) mRNA. Front Neuroanat, 11: 133. [PMID:29403361]
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8. Boels K, Hermans-Borgmeyer I, Schaller HC. (2004) Identification of a mouse orthologue of the G-protein-coupled receptor SALPR and its expression in adult mouse brain and during development. Brain Res Dev Brain Res, 152 (2): 265-8. [PMID:15351514]
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17. Furuya WI, Dhingra RR, Gundlach AL, Hossain MA, Dutschmann M. (2020) Relaxin-3 receptor (RXFP3) activation in the nucleus of the solitary tract modulates respiratory rate and the arterial chemoreceptor reflex in rat. Respir Physiol Neurobiol, 271: 103310. [PMID:31568840]
18. Ganella DE, Callander GE, Ma S, Bye CR, Gundlach AL, Bathgate RA. (2013) Modulation of feeding by chronic rAAV expression of a relaxin-3 peptide agonist in rat hypothalamus. Gene Ther, 20 (7): 703-16. [PMID:23135160]
19. Gay EA, Guan D, Van Voorhies K, Vasukuttan V, Mathews KM, Besheer J, Jin C. (2022) Discovery and Characterization of the First Nonpeptide Antagonists for the Relaxin-3/RXFP3 System. J Med Chem, 65 (11): 7959-7974. [PMID:35594150]
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21. Haidar M, Guèvremont G, Zhang C, Bathgate RAD, Timofeeva E, Smith CM, Gundlach AL. (2017) Relaxin-3 inputs target hippocampal interneurons and deletion of hilar relaxin-3 receptors in "floxed-RXFP3" mice impairs spatial memory. Hippocampus, 27 (5): 529-546. [PMID:28100033]
22. Haidar M, Tin K, Zhang C, Nategh M, Covita J, Wykes AD, Rogers J, Gundlach AL. (2019) Septal GABA and Glutamate Neurons Express RXFP3 mRNA and Depletion of Septal RXFP3 Impaired Spatial Search Strategy and Long-Term Reference Memory in Adult Mice. Front Neuroanat, 13: 30. [PMID:30906254]
23. Haugaard-Kedström LM, Shabanpoor F, Hossain MA, Clark RJ, Ryan PJ, Craik DJ, Gundlach AL, Wade JD, Bathgate RA, Rosengren KJ. (2011) Design, synthesis, and characterization of a single-chain peptide antagonist for the relaxin-3 receptor RXFP3. J Am Chem Soc, 133 (13): 4965-74. [PMID:21384867]
24. Haugaard-Kedström LM, Wong LL, Bathgate RA, Rosengren KJ. (2015) Synthesis and pharmacological characterization of a europium-labelled single-chain antagonist for binding studies of the relaxin-3 receptor RXFP3. Amino Acids, 47 (6): 1267-71. [PMID:25792111]
25. Heidari S, Taromchi AH, Nejatbakhsh R, Shokri S. (2018) Expression and localisation of RXFP3 in human spermatozoa and impact of INSL7 on sperm functions. Andrologia, 50 (3). [PMID:29159832]
26. Hojo K, Hossain MA, Tailhades J, Shabanpoor F, Wong LL, Ong-Pålsson EE, Kastman HE, Ma S, Gundlach AL, Rosengren KJ et al.. (2016) Development of a Single-Chain Peptide Agonist of the Relaxin-3 Receptor Using Hydrocarbon Stapling. J Med Chem, 59 (16): 7445-56. [PMID:27464307]
27. Hosken IT, Sutton SW, Smith CM, Gundlach AL. (2015) Relaxin-3 receptor (Rxfp3) gene knockout mice display reduced running wheel activity: Implications for role of relaxin-3/RXFP3 signalling in sustained arousal. Behav Brain Res, 278: 167-75. [PMID:25257104]
28. Hossain MA, Rosengren KJ, Haugaard-Jönsson LM, Zhang S, Layfield S, Ferraro T, Daly NL, Tregear GW, Wade JD, Bathgate RA. (2008) The A-chain of human relaxin family peptides has distinct roles in the binding and activation of the different relaxin family peptide receptors. J Biol Chem, 283 (25): 17287-97. [PMID:18434306]
29. Hossain MA, Smith CM, Ryan PJ, Büchler E, Bathgate RA, Gundlach AL, Wade JD. (2013) Chemical synthesis and orexigenic activity of rat/mouse relaxin-3. Amino Acids, 44 (6): 1529-36. [PMID:23456488]
30. Hu MJ, Shao XX, Li HZ, Nie WH, Wang JH, Liu YL, Xu ZG, Guo ZY. (2018) Development of a novel ligand binding assay for relaxin family peptide receptor 3 and 4 using NanoLuc complementation. Amino Acids, 50 (8): 1111-1119. [PMID:29770870]
31. Hu MJ, Shao XX, Wang JH, Wei D, Guo YQ, Liu YL, Xu ZG, Guo ZY. (2016) Mechanism for insulin-like peptide 5 distinguishing the homologous relaxin family peptide receptor 3 and 4. Sci Rep, 6: 29648. [PMID:27404393]
32. Hu MJ, Shao XX, Wang JH, Wei D, Liu YL, Xu ZG, Guo ZY. (2016) Identification of hydrophobic interactions between relaxin-3 and its receptor RXFP3: implication for a conformational change in the B-chain C-terminus during receptor binding. Amino Acids, 48 (9): 2227-36. [PMID:27193232]
33. Jayakody T, Marwari S, Lakshminarayanan R, Tan FC, Johannes CW, Dymock BW, Poulsen A, Herr DR, Dawe GS. (2016) Hydrocarbon stapled B chain analogues of relaxin-3 retain biological activity. Peptides, 84: 44-57. [PMID:27498038]
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