RXFP2 | Relaxin family peptide receptors | IUPHAR/BPS Guide to PHARMACOLOGY

RXFP2

Target id: 352

Nomenclature: RXFP2

Family: Relaxin family peptide receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for RXFP2 in GtoImmuPdb

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 754 13q13.1 RXFP2 relaxin family peptide receptor 2 15
Mouse 7 737 5 G3 Rxfp2 relaxin/insulin-like family peptide receptor 2 21
Rat 7 737 12p12 Rxfp2 relaxin family peptide receptor 2 22
Previous and Unofficial Names
GPR106 | RXFPR2 | relaxin receptor 2 | INSL3 receptor | leucine-rich repeat-containing G protein-coupled receptor 8 | LGR8 | relaxin/insulin like family peptide receptor 2
Database Links
Specialist databases
GPCRDB rxfp2_human (Hs), rxfp2_mouse (Mm), q5ecl0_rat (Rn)
Other databases
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
INSL3 {Sp: Human}
relaxin-1 {Sp: Human}
relaxin {Sp: Human}
relaxin-3 {Sp: Human}
Comments: INSL3 is the most potent endogenous agonist. Although human relaxin and relaxin-1 have high affinity for RXFP2 they are unlikely to interact with the receptor physiologically.
Potency order of endogenous ligands (Human)
INSL3 (INSL3, P51460) > relaxin (RLN2, P04090) >> relaxin-3 (RLN3, Q8WXF3)  [19,27]

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
INSL3 {Sp: Human} Hs Full agonist 10.4 pKd 13
pKd 10.4 [13]
[125I]INSL3 (human) Hs Full agonist 10.0 pKd 20
pKd 10.0 [20]
[33P]relaxin (human) Hs Full agonist 9.0 – 9.2 pKd 10,27
pKd 9.0 – 9.2 (Kd 1.06x10-9 – 6.3x10-10 M) [10,27]
europium-labelled INSL3 Hs Full agonist 9.0 pKd 24
pKd 9.0 (Kd 9x10-10 M) [24]
INSL3 {Sp: Human} Hs Full agonist 9.3 – 9.7 pKi 10,13
pKi 9.3 – 9.7 [10,13]
relaxin-1 {Sp: Human} Hs Full agonist 8.8 pKi 1
pKi 8.8 [1]
relaxin {Sp: Human} Hs Full agonist 8.3 – 8.5 pKi 10,13
pKi 8.3 – 8.5 [10,13]
relaxin {Sp: Pig} Hs Full agonist 7.9 pKi 10
pKi 7.9 [10]
relaxin {Sp: Rhesus macaque} Hs Full agonist 7.8 pKi 10
pKi 7.8 [10]
relaxin-3 {Sp: Human} Hs Full agonist 7.0 pKi 1
pKi 7.0 [1]
relaxin {Sp: Human} Hs Full agonist 9.1 pEC50 13
pEC50 9.1 [13]
Agonist Comments
Affinity values were determined in HEK 293 cells expressing human RXFP2.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
A(9-26)INSL3 Hs Antagonist 9.1 pKi 13
pKi 9.1 [13]
A(10-24)INSL3 Hs Antagonist 8.7 pKi 13
pKi 8.7 [13]
A(C10/15S)INSL3 Hs Antagonist 8.6 pKi 29
pKi 8.6 [29]
INSL3 B chain dimer analogue 8 Hs Antagonist 8.5 pKi 25
pKi 8.5 [25]
A(Δ10/15C)INSL3 Hs Antagonist 8.3 pKi 29
pKi 8.3 [29]
cyclic INSL3 B-chain analogue 6 Hs Antagonist 6.7 pKi 23
pKi 6.7 [23]
A(4-24)(B7-24)H2 Hs Antagonist 6.0 pKi 14
pKi 6.0 [14]
INSL3 B-chain analogue Hs Antagonist 5.1 pKi 3
pKi 5.1 (Ki 7.943x10-6 M) [3]
A(4-24)(B7-24)H2 Hs Antagonist 6.0 pEC50 14
pEC50 6.0 [14]
(des 1-8) A-chain INSL3 analogue Hs Antagonist - - 2
[2]
Antagonist Comments
There are now quite a large range of high affinity antagonists available for RXFP2 that contrast strongly with the paucity of antagonists for the closely related RXFP1. This informs the different modes of interaction of relaxin and INSL3 with their respective cognate receptors.
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family
Gi/Go family
Adenylate cyclase stimulation
Adenylate cyclase inhibition
Comments:  RXFP2 couples to a subset of the pathways activated by RXFP1. RXFP2 couples to Gs and GOB but unlike RXFP1 does not couple to Gi3. In some cell types in vivo receptor activation may decrease cAMP levels.
References:  9-10,15-16,19,27
Tissue Distribution
Thyroid.
Species:  Human
Technique:  RT-PCR.
References:  12
Pituitary, testis, kidney.
Species:  Human
Technique:  RT-PCR.
References:  5
Osteoblasts
Species:  Human
Technique:  RT-PCR
References:  4
Prostate
Species:  Human
Technique:  RT-PCR
References:  17
Testis, uterus, brain, kidney, thyroid, muscle, peripheral blood cell, bone marrow.
Species:  Human
Technique:  RT-PCR.
References:  15
Gubernaculum, testis and brain.
Species:  Mouse
Technique:  RT-PCR.
References:  21
Gubernaculum.
Species:  Rat
Technique:  Northern blot.
References:  19
Testis, ovary.
Species:  Rat
Technique:  Northern blot, in situ hybridisation.
References:  16
Kidney.
Species:  Rat
Technique:  RT-PCR, in situ hybridisation.
References:  6
Thalamus.
Species:  Rat
Technique:  RT-PCR, in situ hybridisation.
References:  26
Gubernaculum, testis.
Species:  Rat
Technique:  RT-PCR.
References:  18
Ovary; thecal cells
Species:  Bovine
Technique:  RT-PCR
References:  7
Expression Datasets

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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
Measurement of cAMP levels in HEK 293T cells transfected with RXFP2 receptors.
Species:  Human
Tissue:  HEK 293T cells.
Response measured:  cAMP accumulation.
References:  9-10,15,19,27
Measurement of cAMP levels in cultured gubernacular cells.
Species:  Rat
Tissue:  Gubernaculum.
Response measured:  cAMP accumulation.
References:  19
Growth of organ cultures of day 17 fetal rat gubernaculum.
Species:  Rat
Tissue:  Fetal gubernaculum.
Response measured:  Growth by BrdU incorporation.
References:  18
Responses in bone and osteoblasts
Species:  Human
Tissue:  Bone biopsies, osteoblast cell line, primary osteoblast cultures
Response measured:  cAMP accumulation, proliferation, alterations in specific osteoblast gene expression
References:  4
Physiological Functions
Mediates the transabdominal phase of testicular descent.
Species:  Mouse
Tissue:  Gubernaculum.
References:  8
Oocyte maturation.
Species:  Rat
Tissue:  Oocyte.
References:  16
Male germ cell survival.
Species:  Rat
Tissue:  Male germ cells.
References:  16
Bone formation
Species:  Human
Tissue:  Bone
References:  4
Androgen production in thecal cells
Species:  Bovine
Tissue:  Thecal cells
References:  7
Preantral follicle growth
Species:  Rat
Tissue:  Ovary.
References:  28
Physiological Consequences of Altering Gene Expression
RXFP2 knockout mice develop osteoporosis
Species:  Mouse
Tissue:  Bone
Technique:  Gene knockouts
References:  4
Male mice lacking the RXFP2 receptor demonstrate cryptorchidism due to the failure of the gubernaculum to develop.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  8
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Rxfp2tm1Aia Rxfp2tm1Aia/Rxfp2tm1Aia
involves: 129S7/SvEvBrd * C57BL/6J
MGI:2153463  MP:0005149 abnormal gubernaculum morphology PMID: 12217959 
crsp|Rxfp2+|Rxfp2tm1Aia Rxfp2tm1Aia/crsp
involves: 129S7/SvEvBrd * C57BL/6J * FVB/N
MGI:1313307  MGI:2153463  MP:0005149 abnormal gubernaculum morphology PMID: 12217959 
Rxfp2tm1Aia Rxfp2tm1Aia/Rxfp2tm1Aia
involves: 129S7/SvEvBrd * C57BL/6J
MGI:2153463  MP:0003673 abnormal inguinal canal morphology PMID: 12217959 
Rxfp1tm1Aia|Rxfp2tm1Aia Rxfp1tm1Aia/Rxfp1tm1Aia,Rxfp2tm1Aia/Rxfp2tm1Aia
involves: 129S7/SvEvBrd * C57BL/6J
MGI:2153463  MGI:2682211  MP:0001882 abnormal lactation PMID: 15256493 
Rxfp1tm1Aia|Rxfp2tm1Aia Rxfp1tm1Aia/Rxfp1tm1Aia,Rxfp2tm1Aia/Rxfp2tm1Aia
involves: 129S7/SvEvBrd * C57BL/6J
MGI:2153463  MGI:2682211  MP:0006078 abnormal nipple morphology PMID: 15256493 
crsp|Rxfp2+|Rxfp2tm1Aia Rxfp2tm1Aia/crsp
involves: 129S7/SvEvBrd * C57BL/6J * FVB/N
MGI:1313307  MGI:2153463  MP:0009213 absent male inguinal canal PMID: 12217959 
Rxfp2tm1Aia Rxfp2tm1Aia/Rxfp2tm1Aia
involves: 129S7/SvEvBrd * C57BL/6J
MGI:2153463  MP:0001155 arrest of spermatogenesis PMID: 12217959 
crsp|Rxfp2+|Rxfp2tm1Aia Rxfp2tm1Aia/crsp
involves: 129S7/SvEvBrd * C57BL/6J * FVB/N
MGI:1313307  MGI:2153463  MP:0001155 arrest of spermatogenesis PMID: 12217959 
Rxfp2tm1Aia Rxfp2tm1Aia/Rxfp2tm1Aia
involves: 129S7/SvEvBrd * C57BL/6J
MGI:2153463  MP:0005159 azoospermia PMID: 12217959 
crsp|Rxfp2+|Rxfp2tm1Aia Rxfp2tm1Aia/crsp
involves: 129S7/SvEvBrd * C57BL/6J * FVB/N
MGI:1313307  MGI:2153463  MP:0005159 azoospermia PMID: 12217959 
Rxfp2tm1Aia Rxfp2tm1Aia/Rxfp2tm1Aia
involves: 129S7/SvEvBrd * C57BL/6J
MGI:2153463  MP:0002286 cryptorchism PMID: 12217959 
Rxfp1tm1Aia|Rxfp2tm1Aia Rxfp1tm1Aia/Rxfp1tm1Aia,Rxfp2tm1Aia/Rxfp2tm1Aia
involves: 129S7/SvEvBrd * C57BL/6J
MGI:2153463  MGI:2682211  MP:0002286 cryptorchism PMID: 15256493 
crsp|Rxfp2+|Rxfp2tm1Aia Rxfp2tm1Aia/crsp
involves: 129S7/SvEvBrd * C57BL/6J * FVB/N
MGI:1313307  MGI:2153463  MP:0002286 cryptorchism PMID: 12217959 
Rxfp2tm1Aia Rxfp2tm1Aia/Rxfp2tm1Aia
involves: 129S7/SvEvBrd * C57BL/6J
MGI:2153463  MP:0001925 male infertility PMID: 12217959 
crsp|Rxfp2+|Rxfp2tm1Aia Rxfp2tm1Aia/crsp
involves: 129S7/SvEvBrd * C57BL/6J * FVB/N
MGI:1313307  MGI:2153463  MP:0001925 male infertility PMID: 12217959 
Rxfp2tm1Aia Rxfp2tm1Aia/Rxfp2tm1Aia
involves: 129S7/SvEvBrd * C57BL/6J
MGI:2153463  MP:0001147 small testis PMID: 12217959 
crsp|Rxfp2+|Rxfp2tm1Aia Rxfp2tm1Aia/crsp
involves: 129S7/SvEvBrd * C57BL/6J * FVB/N
MGI:1313307  MGI:2153463  MP:0001147 small testis PMID: 12217959 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Cryptorchidism
Disease Ontology: DOID:11383
References:  11
Disease:  Osteoporosis
Disease Ontology: DOID:11476
OMIM: 166710
Role: 
References:  4

References

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1. 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]

2. Büllesbach EE, Schwabe C. (2005) LGR8 signal activation by the relaxin-like factor. J Biol Chem, 280: 14586-14590. [PMID:15708846]

3. Del Borgo MP, Hughes RA, Bathgate RA, Lin F, Kawamura K, Wade JD. (2006) Analogs of insulin-like peptide 3 (INSL3) B-chain are LGR8 antagonists in vitro and in vivo. J Biol Chem,: 727-729. [PMID:16547350]

4. Ferlin A, Pepe A, Gianesello L, Garolla A, Feng S, Facciolli A, Morello R, Agoulnik AI, Foresta C. (2009) New roles for INSL3 in adults. Ann. N. Y. Acad. Sci., 1160: 215-8. [PMID:19416191]

5. Foresta C, Ferlin A. (2004) Role of INSL3 and LGR8 in cryptorchidism and testicular functions. Reprod Biomed Online, 9: 294-298. [PMID:15353080]

6. Fu P, Shen PJ, Zhao CX, Scott DJ, Samuel CS, Wade JD, Tregear GW, Bathgate RA, Gundlach AL. (2005) Detection, localization, and action of the INSL3 receptor, LGR8, in rat kidney. Ann N Y Acad Sci, 1041: 516-519. [PMID:15956754]

7. Glister C, Satchell L, Bathgate RA, Wade JD, Dai Y, Ivell R, Anand-Ivell R, Rodgers RJ, Knight PG. (2013) Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production. Proc. Natl. Acad. Sci. U.S.A., 110 (15): E1426-35. [PMID:23530236]

8. Gorlov IP, Kamat A, Bogatcheva NV, Jones E, Lamb DJ, Truong A, Bishop CE, McElreavey K, Agoulnik AI. (2002) Mutations of the GREAT gene cause cryptorchidism. Hum Mol Genet, 11: 2309-2318. [PMID:12217959]

9. Halls ML, Bathgate RA, Summers RJ. (2006) Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP signaling by distinct mechanisms. Mol. Pharmacol., 70 (1): 214-26. [PMID:16569707]

10. Halls ML, Bond CP, Sudo S, Kumagai J, Ferraro T, Layfield S, Bathgate RA, Summers RJ. (2005) Multiple binding sites revealed by interaction of relaxin family peptides with native and chimeric relaxin family peptide receptors 1 and 2 (LGR7 and LGR8). J Pharmacol Exp Ther, 313: 677-687. [PMID:15649866]

11. Harris RM, Finlayson C, Weiss J, Fisher L, Hurley L, Barrett T, Emge D, Bathgate RA, Agoulnik AI, Jameson JL. (2010) A missense mutation in LRR8 of RXFP2 is associated with cryptorchidism. Mamm. Genome, 21 (9-10): 442-9. [PMID:20963592]

12. Hombach-Klonisch S, Hoang-Vu C, Kehlen A, Hinze R, Holzhausen HJ, Weber E, Fischer B, Dralle H, Klonisch T. (2003) INSL-3 is expressed in human hyperplastic and neoplastic thyrocytes. Int J Oncol, 22: 993-1001. [PMID:12684664]

13. 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]

14. Hossain MA, Rosengren KJ, Samuel CS, Shabanpoor F, Chan LJ, Bathgate RA, Wade JD. (2011) The minimal active structure of human relaxin-2. J. Biol. Chem., 286 (43): 37555-65. [PMID:21878627]

15. Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ. (2002) Activation of orphan receptors by the hormone relaxin. Science, 295: 671-674. [PMID:11809971]

16. Kawamura K, Kumagai J, Sudo S, Chun SY, Pisarska M, Morita H, Toppari J, Fu P, Wade JD, Bathgate RA, Hsueh AJ. (2004) Paracrine regulation of mammalian oocyte maturation and male germ cell survival. Proc Natl Acad Sci U S A, 101: 7323-7328. [PMID:15123806]

17. Klonisch T, Müller-Huesmann H, Riedel M, Kehlen A, Bialek J, Radestock Y, Holzhausen HJ, Steger K, Ludwig M, Weidner W et al.. (2005) INSL3 in the benign hyperplastic and neoplastic human prostate gland. Int. J. Oncol., 27 (2): 307-15. [PMID:16010410]

18. Kubota Y, Temelcos C, Bathgate RA, Smith KJ, Scott D, Zhao C, Hutson JM. (2002) The role of insulin 3, testosterone, Müllerian inhibiting substance and relaxin in rat gubernacular growth. Mol Hum Reprod, 8: 900-905. [PMID:12356938]

19. Kumagai J, Hsu SY, Matsumi H, Roh JS, Fu P, Wade JD, Bathgate RA, Hsueh AJ. (2002) INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. J Biol Chem, 277: 31283-31286. [PMID:12114498]

20. Muda M, He C, Martini PG, Ferraro T, Layfield S, Taylor D, Chevrier C, Schweickhardt R, Kelton C, Ryan PL, Bathgate RA. (2005) Splice variants of the relaxin and INSL3 receptors reveal unanticipated molecular complexity. Mol Hum Reprod, 11: 591-600. [PMID:16051677]

21. Overbeek PA, Gorlov IP, Sutherland RW, Houston JB, Harrison WR, Boettger-Tong HL, Bishop CE, Agoulnik AI. (2001) A transgenic insertion causing cryptorchidism in mice. Genesis, 30: 26-35. [PMID:11353515]

22. Scott DJ, Fu P, Shen PJ, Gundlach A, Layfield S, Riesewijk A, Tomiyama H, Hutson JM, Tregear GW, Bathgate RA. (2005) Characterization of the rat INSL3 receptor. Ann N Y Acad Sci, 1041: 13-16. [PMID:15956681]

23. Shabanpoor F, Bathgate RA, Hossain MA, Giannakis E, Wade JD, Hughes RA. (2007) Design, synthesis and pharmacological evaluation of cyclic mimetics of the insulin-like peptide 3 (INSL3) B-chain. J. Pept. Sci., 13 (2): 113-20. [PMID:17120268]

24. Shabanpoor F, Hughes RA, Bathgate RA, Zhang S, Scanlon DB, Lin F, Hossain MA, Separovic F, Wade JD. (2008) Solid-phase synthesis of europium-labeled human INSL3 as a novel probe for the study of ligand-receptor interactions. Bioconjug. Chem., 19 (7): 1456-63. [PMID:18529069]

25. Shabanpoor F, Zhang S, Hughes RA, Hossain MA, Layfield S, Ferraro T, Bathgate RA, Separovic F, Wade JD. (2011) Design and development of analogues of dimers of insulin-like peptide 3 B-chain as high-affinity antagonists of the RXFP2 receptor. Biopolymers, 96 (1): 81-7. [PMID:20560146]

26. Shen PJ, Fu P, Phelan KD, Scott DJ, Layfield S, Tregear GW, Bathgate RA, Gundlach AL. (2005) Restricted expression of LGR8 in intralaminar thalamic nuclei of rat brain suggests a role in sensorimotor systems. Ann N Y Acad Sci, 1041: 510-515. [PMID:15956753]

27. Sudo S, Kumagai J, Nishi S, Layfield S, Ferraro T, Bathgate RA, Hsueh AJ. (2003) H3 relaxin is a specific ligand for LGR7 and activates the receptor by interacting with both the ectodomain and the exoloop 2. J Biol Chem, 278: 7855-7862. [PMID:12506116]

28. Xue K, Kim JY, Liu JY, Tsang BK. (2014) Insulin-like 3-induced rat preantral follicular growth is mediated by growth differentiation factor 9. Endocrinology, 155 (1): 156-67. [PMID:24169563]

29. Zhang S, Hughes RA, Bathgate RA, Shabanpoor F, Hossain MA, Lin F, van Lierop B, Robinson AJ, Wade JD. (2010) Role of the intra-A-chain disulfide bond of insulin-like peptide 3 in binding and activation of its receptor, RXFP2. Peptides, 31 (9): 1730-6. [PMID:20570702]

Contributors

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How to cite this page

Roger Summers, Michelle Halls, Ross Bathgate, Thomas Dschietzig, Andrew L. Gundlach.
Relaxin family peptide receptors: RXFP2. Last modified on 20/02/2018. Accessed on 17/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=352.