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RXFP4

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Target not currently curated in GtoImmuPdb

Target id: 354

Nomenclature: RXFP4

Family: Relaxin family peptide receptors

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 374 1q22 RXFP4 relaxin family peptide/INSL5 receptor 4 11
Mouse 7 414 3 F1 Rxfp4 relaxin family peptide receptor 4 5
Gene and Protein Information Comments
Present in rats as a pseudogene.
Previous and Unofficial Names Click here for help
RLN3R2 | GPCR142 | INSL5 receptor | RXFPR4 | G protein-coupled receptor 100 | relaxin/insulin-like family peptide receptor 4 | relaxin/insulin like family peptide receptor 4
Database Links Click here for help
Specialist databases
GPCRDB rl3r2_human (Hs), rl3r2_mouse (Mm)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands Click here for help
INSL5 {Sp: Human} , INSL5 {Sp: Mouse}
relaxin-3 {Sp: Human}
Potency order of endogenous ligands (Human)
INSL5 (INSL5, Q9Y5Q6) = relaxin-3 (RLN3, Q8WXF3) > relaxin-3 (B chain) (RLN3, Q8WXF3)  [10-11]

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[125I]relaxin-3 (human) Peptide Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist 8.7 – 9.7 pKd 11
pKd 8.7 – 9.7 (Kd 2x10-9 – 2x10-10 M) [11]
[125I]relaxin-3-B/INSL5 A chimera Peptide Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Agonist 8.9 pKd 10
pKd 8.9 (Kd 1.2x10-9 M) [10]
[125I]INSL5 (human) Peptide Ligand is labelled Ligand is radioactive Hs Full agonist 8.6 pKd 12
pKd 8.6 [12]
europium-labelled mouse INSL5 Peptide Ligand is labelled Mm Full agonist 8.6 pKd 2
pKd 8.6 [2]
europium-labelled relaxin-3-B/INSL5 A chimera Peptide Click here for species-specific activity table Ligand is labelled Hs Agonist 8.3 pKd 7
pKd 8.3 (Kd 5x10-9 M) [7]
europium-labelled mouse INSL5 Peptide Ligand is labelled Hs Agonist 8.3 pKd 3
pKd 8.3 (Kd 5x10-9 M) [3]
relaxin-3 {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 8.8 – 9.0 pKi 9,11,16
pKi 9.0 [11]
pKi 8.8 – 8.8 [9,16]
R3/I5 Peptide Click here for species-specific activity table Hs Full agonist 8.9 pKi 9
pKi 8.9 [9]
INSL5 {Sp: Mouse} Peptide Ligand is endogenous in the given species Mm Full agonist 8.5 – 8.8 pKi 2,14
pKi 8.5 – 8.8 [2,14]
INSL5 {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 7.3 – 8.8 pKi 2,12,14-16
pKi 7.3 – 8.8 [2,12,14-16]
hINSL5: A8-21 (T9R) Peptide Hs Full agonist 7.5 pKi
pKi 7.5
minimised relaxin-3 analogue 2 Peptide Click here for species-specific activity table Hs Full agonist 7.1 pKi 15
pKi 7.1 [15]
INSL5 amide (mouse) Peptide Mm Full agonist 7.1 pKi 3
pKi 7.1 [3]
INSL5 amide (human) Peptide Hs Full agonist 6.9 pKi 3
pKi 6.9 [3]
minimised INSL5 analogue 7 Peptide Hs Partial agonist 6.3 pKi 2
pKi 6.3 [2]
relaxin-3 {Sp: Human} Peptide Click here for species-specific activity table Hs Full agonist 9.0 pEC50 16
pEC50 9.0 [16]
R3/I5 Peptide Click here for species-specific activity table Hs Full agonist 8.9 pEC50 9
pEC50 8.9 [9]
INSL5 {Sp: Mouse} Peptide Mm Full agonist 7.8 – 8.9 pEC50 1
pEC50 7.8 – 8.9 [1]
INSL5 {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 7.0 – 8.9 pEC50 1,8,12
pEC50 8.9 – 8.9 [8,12]
pEC50 7.0 – 7.7 [1]
relaxin-3 (B chain) {Sp: Human} Peptide Click here for species-specific activity table Hs Partial agonist 7.0 pEC50 11
pEC50 7.0 [11]
INSL5 {Sp: Mouse} Peptide Ligand is endogenous in the given species Mm Full agonist 9.3 pIC50 2,14
pIC50 9.3 [2,14]
relaxin-3 {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 9.0 pIC50 9
pIC50 9.0 [9]
INSL5 {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 8.3 – 8.9 pIC50 2,12,14-15
pIC50 8.3 – 8.9 [2,12,14-15]
minimised relaxin-3 analogue 2 Peptide Click here for species-specific activity table Hs Full agonist 7.7 pIC50 15
pIC50 7.7 [15]
hINSL5: A8-21 (T9R) Peptide Hs Full agonist 7.7 pIC50 14
pIC50 7.7 [14]
INSL5 amide (human) Peptide Hs Full agonist 7.5 pIC50 3
pIC50 7.5 [3]
minimised INSL5 analogue 7 Peptide Hs Partial agonist 7.4 pIC50 2
pIC50 7.4 [2]
relaxin-3 (B chain) {Sp: Human} Peptide Click here for species-specific activity table Hs Partial agonist 6.9 – 7.1 pIC50 11-12
pIC50 6.9 – 7.1 [11-12]
INSL5 amide (mouse) Peptide Mm Full agonist 6.8 pIC50 3
pIC50 6.8 [3]
View species-specific agonist tables
Agonist Comments
Affinity values were determined in COS-7 cells expressing human RXFP4. Amidated peptides are much less potent than the native peptides. Mouse orthologues are generally more potent than the human peptide at human RXFP4 although recent studies suggest that this may be related to some extent to different purity of peptides rather than generic differences in potency. Although a potent agonist at RXFP4, relaxin-3 is unlikely to be a physiological ligand due to mismatch of expression patterns of peptide and receptor. In addition to inhibition of cAMP accumulation, RXFP4 is now known to cause phosphorylation of ERK1/2, p38MAPK, Akt Ser473 and Thr308, and S6RP [1].
Antagonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
R3(BΔ23-27)R/I5 chimeric peptide Peptide Click here for species-specific activity table Hs Antagonist 8.0 – 8.6 pIC50 7,9
pIC50 8.0 – 8.6 [7,9]
minimised relaxin-3 analogue 3 Peptide Click here for species-specific activity table Hs Antagonist 6.6 pIC50 15
pIC50 6.6 [15]
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Other - See Comments
Comments:  Phosphorylation of ERK1/2, p38MAPK, Akt Ser473 and Thr308, and S6RP [1].
References:  1,10-12
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Calcium channel
Other - See Comments
Comments:  Calcium signalling is only activated in cells co-expressing the promiscuous G protein Gα16. RXFP4 causes pERK1/2 activation in MIN6 and GLUTag cells in response to INSL5 in single dose studies, but also in CHO cells expressing RXFP4 in which p38MAPK, Akt and S6RP are also activated [1].
References:  1,12-13
Tissue Distribution Click here for help
Stomach, fetal brain, brain, leukocytes, kidney, colon, prostate, lung, ovary, thymus, thyroid, placenta, spleen, pituitary, heart.
Species:  Human
Technique:  RT-PCR.
References:  12
Colon, thyroid, salivary gland, prostate, placenta, thymus, testis, kidney, brain.
Species:  Human
Technique:  RT-PCR.
References:  11
Ovary, uterus, testis, prostate, brain, heart, intestine, colon, adrenal, thyroid, thymus, salivary gland, muscle, peripheral blood cells, bone marrow.
Species:  Human
Technique:  Multi-tissue expression array.
References:  4
Colon, caecum, nodose ganglion
Species:  Mouse
Technique:  RT-PCR
References:  6
Myenteric and submucosal plexus
Species:  Mouse
Technique:  In situ hybridisation
References:  6
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
GLP-1 release
Species:  Mouse
Tissue:  GLUTag cells
Response measured:  Increased secretion of GLP-1
References:  13
Measurement of cAMP levels in COS-7 cells transiently transfected with RXFP4 receptors. cAMP indicated by pCRE reporter gene.
Species:  Human
Tissue:  COS-7 cells.
Response measured:  pCRE reporter gene inhibition
References:  10-12
Inhibition of pCRE reporter gene activation by forskolin
Species:  Mouse
Tissue:  HEK293 cells transiently expressing mouse RXFP4
Response measured:  Inhibition of pCRE reporter gene activation
References:  13
Inhibition of pCRE reporter gene activation by forskolin
Species:  Human
Tissue:  HEK293 cells transiently expressing human RXFP4
Response measured:  Inhibition of pCRE reporter gene activation
References:  13
Insulin secretion
Species:  Mouse
Tissue:  MIN6 insulinoma cells
Response measured:  Increased insulin secretion
References:  13
ERK1/2 activation
Species:  Human
Tissue:  HEK293 cells transiently expressing human RXFP4
Response measured:  Increased phosphorylation of ERK1/2
References:  13
ERK1/2 activation
Species:  Mouse
Tissue:  HEK293 cells transiently expressing mouse RXFP4
Response measured:  Increased phosphorylation of ERK1/2
References:  13
Inhibition of pCRE reporter gene activation by forskolin
Species:  Human
Tissue:  CHO cells stably or transiently expressing RXFP4
Response measured:  Inhibition of pCRE reporter gene activation
References:  2-3,9,11-12,15
Inhibition of pCRE reporter gene activation by forskolin
Species:  Human
Tissue:  SK-N-MC cells transfected with pCRE reporter
Response measured:  Inhibition of pCRE reporter gene activation
References:  9
GTPγS binding
Species:  Human
Tissue:  COS-7 cells transiently expressing RXFP4
Response measured:  Increased GTPγS binding
References:  9,11-12
ERK1/2 activation
Species:  Human
Tissue:  CHO cells stably expressing human RXFP4
Response measured:  Increased phosphorylation of ERK1/2
References:  1
S6RP activation
Species:  Human
Tissue:  CHO cells stably expressing human RXFP4
Response measured:  Increased phosphorylation of S6RP
References:  1
p38MAPK activation
Species:  Human
Tissue:  CHO cells stably expressing human RXFP4
Response measured:  Increased phosphorylation of p38MAPK
References:  1
Akt activation
Species:  Human
Tissue:  CHO cells stably expressing human RXFP4
Response measured:  Increased hosphorylation of Akt Ser473 and Thr308
References:  1
Insulin secretion
Species:  Mouse
Tissue:  MIN6 insulinoma cells
Response measured:  Inhibition of glucose stimulated insulin secretion
References:  1
cAMP accumulation
Species:  Human
Tissue:  NCI-H716 cells
Response measured:  Inhibition of forskolin-stimulated cAMP accumulation
References:  1
Physiological Functions Click here for help
Stimulation of food intake
Species:  Mouse
Tissue:  Orexigenic action in mouse
References:  6
Physiological Consequences of Altering Gene Expression Click here for help
RXFP4 knockout mice do not display orexigeneic action of INSL5
Species:  Mouse
Tissue: 
Technique:  Gene knockouts
References:  6

References

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1. Ang SY, Hutchinson DS, Patil N, Evans BA, Bathgate RAD, Halls ML, Hossain MA, Summers RJ, Kocan M. (2017) Signal transduction pathways activated by insulin-like peptide 5 at the relaxin family peptide RXFP4 receptor. Br. J. Pharmacol., 174 (10): 1077-1089. [PMID:27243554]

2. Belgi A, Bathgate RA, Kocan M, Patil N, Zhang S, Tregear GW, Wade JD, Hossain MA. (2013) Minimum active structure of insulin-like peptide 5. J. Med. Chem., 56 (23): 9509-16. [PMID:24188028]

3. Belgi A, Hossain MA, Shabanpoor F, Chan L, Zhang S, Bathgate RA, Tregear GW, Wade JD. (2011) Structure and function relationship of murine insulin-like peptide 5 (INSL5): free C-terminus is essential for RXFP4 receptor binding and activation. Biochemistry, 50 (39): 8352-61. [PMID:21866895]

4. Boels K, Schaller HC. (2003) Identification and characterisation of GPR100 as a novel human G-protein-coupled bradykinin receptor. Br. J. Pharmacol., 140 (5): 932-8. [PMID:14530218]

5. Chen J, Kuei C, Sutton SW, Bonaventure P, Nepomuceno D, Eriste E, Sillard R, Lovenberg TW, Liu C. (2005) Pharmacological characterization of relaxin-3/INSL7 receptors GPCR135 and GPCR142 from different mammalian species. J. Pharmacol. Exp. Ther., 312 (1): 83-95. [PMID:15367576]

6. Grosse J, Heffron H, Burling K, Akhter Hossain M, Habib AM, Rogers GJ, Richards P, Larder R, Rimmington D, Adriaenssens AA et al.. (2014) Insulin-like peptide 5 is an orexigenic gastrointestinal hormone. Proc. Natl. Acad. Sci. U.S.A., 111 (30): 11133-8. [PMID:25028498]

7. 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]

8. Khalaf MS, Coles MP, Hitchcock PB. (2008) A structural, theoretical and coordinative evaluation of the bicyclic guanidinate derived from 1,4,6-triazabicyclo[3.3.0]oct-4-ene. Dalton Trans, (32): 4288-95. [PMID:18682868]

9. Kuei C, Sutton S, Bonaventure P, Pudiak C, Shelton J, Zhu J, Nepomuceno D, Wu J, Chen J, Kamme F et al.. (2007) R3(BDelta23 27)R/I5 chimeric peptide, a selective antagonist for GPCR135 and GPCR142 over relaxin receptor LGR7: in vitro and in vivo characterization. J. Biol. Chem., 282 (35): 25425-35. [PMID:17606621]

10. Liu C, Chen J, Kuei C, Sutton S, Nepomuceno D, Bonaventure P, Lovenberg TW. (2005) Relaxin-3/insulin-like peptide 5 chimeric peptide, a selective ligand for G protein-coupled receptor (GPCR)135 and GPCR142 over leucine-rich repeat-containing G protein-coupled receptor 7. Mol. Pharmacol., 67 (1): 231-40. [PMID:15465925]

11. Liu C, Chen J, Sutton S, Roland B, Kuei C, Farmer N, Sillard R, Lovenberg TW. (2003) Identification of relaxin-3/INSL7 as a ligand for GPCR142. J. Biol. Chem., 278 (50): 50765-70. [PMID:14522967]

12. Liu C, Kuei C, Sutton S, Chen J, Bonaventure P, Wu J, Nepomuceno D, Kamme F, Tran DT, Zhu J et al.. (2005) INSL5 is a high affinity specific agonist for GPCR142 (GPR100). J. Biol. Chem., 280 (1): 292-300. [PMID:15525639]

13. Luo X, Li T, Zhu Y, Dai Y, Zhao J, Guo ZY, Wang MW. (2015) The insulinotrophic effect of insulin-like peptide 5 in vitro and in vivo. Biochem. J., 466 (3): 467-73. [PMID:25514935]

14. Patil NA, Hughes RA, Rosengren KJ, Kocan M, Ang SY, Tailhades J, Separovic F, Summers RJ, Grosse J, Wade JD et al.. (2016) Engineering of a Novel Simplified Human Insulin-Like Peptide 5 Agonist. J. Med. Chem., 59 (5): 2118-25. [PMID:26824523]

15. Shabanpoor F, Akhter Hossain M, Ryan PJ, Belgi A, Layfield S, Kocan M, Zhang S, Samuel CS, Gundlach AL, Bathgate RA et al.. (2012) Minimization of human relaxin-3 leading to high-affinity analogues with increased selectivity for relaxin-family peptide 3 receptor (RXFP3) over RXFP1. J. Med. Chem., 55 (4): 1671-81. [PMID:22257012]

16. Zhu J, Kuei C, Sutton S, Kamme F, Yu J, Bonaventure P, Atack J, Lovenberg TW, Liu C. (2008) Identification of the domains in RXFP4 (GPCR142) responsible for the high affinity binding and agonistic activity of INSL5 at RXFP4 compared to RXFP3 (GPCR135). Eur. J. Pharmacol., 590 (1-3): 43-52. [PMID:18582868]

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