Skip to main content
SpringerLink
Log in
Book cover

Encyclopedia of Signaling Molecules pp 1–32Cite as

Relaxin Family Peptide Receptors RXFP1 and RXFP2

  • Living reference work entry
  • First Online:

  • 75 Accesses

Synonyms

GREAT; LGR7; LGR8; RXFP1; RXFP2

Historical Background: Relaxin Family Peptides and Their Receptors

Relaxin was one of the first reproductive hormones to be identified, as a factor in the serum of pregnant guinea pigs that induced relaxation of the birth canal (Hisaw 1926). Until recently, relaxin was considered a hormone of pregnancy with little known of its roles in males and nonpregnant females. The isolation of relaxin from animal sources led to the determination of its structure, biological actions, and development of reliable bioassays (Schwabe and McDonald 1977; James et al. 1977; John et al. 1981), and this knowledge led to the use of recombinant DNA techniques to clone the rat (Hudson et al. 1981), pig (Haley et al. 1982), and human gene-1 (RLN1) (Hudson et al. 1983) and gene-2 relaxin (RLN2) genes (Hudson et al. 1984). The identification of other relaxin peptides and their cognate G protein-coupled receptors (GPCRs), more than 75 years after the identification of the...

This is a preview of subscription content, log in via an institution.

References

  • Adham IM, Burkhardt E, Benahmed M, Engel W. Cloning of a cDNA for a novel insulin-like peptide of the testicular Leydig cells. J Biol Chem. 1993;268(35):26668–72.

    CAS  PubMed  Google Scholar 

  • Ahmad N, Wang W, Nair R, Kapila S. Relaxin induces matrix-metalloproteinases-9 and -13 via RXFP1: induction of MMP-9 involves the PI3K, ERK, Akt and PKC-zeta pathways. Mol Cell Endocrinol. 2012;363(1–2):46–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alexiou K, Matschke K, Westphal A, Stangl K, Dschietzig T. Relaxin is a candidate drug for lung preservation: relaxin-induced protection of rat lungs from ischemia-reperfusion injury. J Heart Lung Transplant. 2010;29(4):454–60.

    Article  PubMed  Google Scholar 

  • Alexiou K, Wilbring M, Matschke K, Dschietzig T. 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. 2013;8(9):e75592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anand-Ivell RJ, Relan V, Balvers M, Coiffec-Dorval I, Fritsch M, Bathgate RA, et al. Expression of the insulin-like peptide 3 (INSL3) hormone-receptor (LGR8) system in the testis. Biol Reprod. 2006;74(5):945–53.

    Article  CAS  PubMed  Google Scholar 

  • Anand-Ivell RJK, Heng K, Bartsch O, Ivell R. Relaxin signalling in THP-1 cells uses a novel phosphotyrosine-dependent pathway. Mol Cell Endocrinol. 2007;272:1–13.

    Article  CAS  PubMed  Google Scholar 

  • Anand-Ivell R, Tremellen K, Dai Y, Heng K, Yoshida M, Knight PG, et al. Circulating insulin-like factor 3 (INSL3) in healthy and infertile women. Hum Reprod. 2013;28(11):3093–102.

    Article  CAS  PubMed  Google Scholar 

  • Ascoli M, Fanelli F, Segaloff DL. The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev. 2002;23(2):141–74.

    Article  CAS  PubMed  Google Scholar 

  • Baccari MC, Bani D, Bigazzi M, Calamai F. Influence of relaxin on the neurally induced relaxant responses of the mouse gastric fundus. Biol Reprod. 2004;71(4):1325–9.

    Article  CAS  PubMed  Google Scholar 

  • Baccari MC, Nistri S, Vannucchi MG, Calamai F, Bani D. Reversal by relaxin of altered ileal spontaneous contractions in dystrophic (mdx) mice through a nitric oxide-mediated mechanism. Am J Phys Regul Integr Comp Phys. 2007;293(2):R662–8.

    CAS  Google Scholar 

  • Bani D. Relaxin and breast cancer. Bull Cancer. 1997;84(2):179–82.

    CAS  PubMed  Google Scholar 

  • Bani G, Bani ST, Bigazzi M, Bianchi S. Effects of relaxin on the microvasculature of mouse mammary gland. Histol Histopathol. 1988;3(4):337–43.

    CAS  PubMed  Google Scholar 

  • Bani D, Failli P, Bello MG, Thiemermann C, Bani Sacchi T, Bigazzi M, et al. Relaxin activates the L-arginine-nitric oxide pathway in vascular smooth muscle cells in culture. Hypertension. 1998a;31(6):1240–7.

    Article  CAS  PubMed  Google Scholar 

  • Bani D, Masini E, Bello MG, Bigazzi M, Sacchi TB. Relaxin protects against myocardial injury caused by ischemia and reperfusion in rat heart. Am J Pathol. 1998b;152(5):1367–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bani D, Nistri S, Quattrone S, Bigazzi M, Sacchi TB. Relaxin causes changes of the liver. In vivo studies in rats. Horm Metab Res. 2001;33(3):175–80.

    Article  CAS  PubMed  Google Scholar 

  • Bani-Sacchi T, Bigazzi M, Bani D, Mannaioni PF, Masini E. Relaxin-induced increased coronary flow through stimulation of nitric oxide production. Br J Pharmacol. 1995;116:1589–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bartsch O, Bartlick B, Ivell R. Relaxin signalling links tyrosine phosphorylation to phosphodiesterase and adenylyl cyclase activity. Mol Hum Reprod. 2001;7(9):799–809.

    Article  CAS  PubMed  Google Scholar 

  • Bathgate R, Balvers M, Hunt N, Ivell R. Relaxin-like factor gene is highly expressed in the bovine ovary of the cycle and pregnancy: sequence and messenger ribonucleic acid analysis. Biol Reprod. 1996;55:1452–7.

    Article  CAS  PubMed  Google Scholar 

  • Bathgate R, Moniac N, Bartlick B, Schumacher M, Fields M, Ivell R. Expression and regulation of relaxin-like factor gene transcripts in the bovine ovary: differentiation-dependent expression in theca cell cultures. Biol Reprod. 1999;61:1090–8.

    Article  CAS  PubMed  Google Scholar 

  • Bathgate RAD, Hsueh AJW, Sherwood OD. Physiology and molecular biology of the relaxin peptide family. In: Neill JD, editor. Knobil and Neill’s physiology of reproduction. 3rd ed. Boston: Academic; 2006a.

    Google Scholar 

  • Bathgate RA, Lin F, Hanson NF, Otvos Jr L, Guidolin A, Giannakis C, et al. Relaxin-3: improved synthesis strategy and demonstration of its high-affinity interaction with the relaxin receptor LGR7 both in vitro and in vivo. Biochemistry. 2006b;45(3):1043–53.

    Article  CAS  PubMed  Google Scholar 

  • Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ. International Union of Pharmacology LVII: recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev. 2006c;58(1):7–31.

    Article  CAS  PubMed  Google Scholar 

  • Bathgate RA, Lekgabe ED, McGuane JT, Su Y, Pham T, Ferraro T, et al. Adenovirus-mediated delivery of relaxin reverses cardiac fibrosis. Mol Cell Endocrinol. 2008;280(1–2):30–8.

    Article  CAS  PubMed  Google Scholar 

  • Bathgate RA, Halls ML, van der Westhuizen ET, Callander GE, Kocan M, Summers RJ. Relaxin family peptides and their receptors. Physiol Rev. 2013;93(1):405–80.

    Article  CAS  PubMed  Google Scholar 

  • Bennett RG. Relaxin and its role in the development and treatment of fibrosis. Transl Res. 2009;154(1):1–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhushan S, Kondo K, Polhemus DJ, Otsuka H, Nicholson CK, Tao YX, et al. Nitrite therapy improves left ventricular function during heart failure via restoration of nitric oxide-mediated cytoprotective signaling. Circ Res. 2014;114(8):1281–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bialek J, Kunanuvat U, Hombach-Klonisch S, Spens A, Stetefeld J, Sunley K, et al. Relaxin enhances the collagenolytic activity and in vitro invasiveness by upregulating matrix metalloproteinases in human thyroid carcinoma cells. Mol Cancer Res. 2011;9(6):673–87.

    Article  CAS  PubMed  Google Scholar 

  • Bigazzi M, Del MA, Petrucci F, Casali R, Novelli GP. The local administration of relaxin induces changes in the microcirculation of the rat mesocaecum. Acta Endocrinol Copenh. 1986;112(2):296–9.

    CAS  PubMed  Google Scholar 

  • Binder C, Hagemann T, Husen B, Schulz M, Einspanier A. Relaxin enhances in-vitro invasiveness of breast cancer cell lines by up-regulation of matrix metalloproteases. Mol Hum Reprod. 2002;8(9):789–96.

    Article  CAS  PubMed  Google Scholar 

  • Binder C, Simon A, Binder L, Hagemann T, Schulz M, Emons G, et al. Elevated concentrations of serum relaxin are associated with metastatic disease in breast cancer patients. Breast Cancer Res Treat. 2004;87(2):157–66.

    Article  CAS  PubMed  Google Scholar 

  • Bitto A, Irrera N, Minutoli L, Calo M, Lo Cascio P, Caccia P, et al. Relaxin improves multiple markers of wound healing and ameliorates the disturbed healing pattern of genetically diabetic mice. Clin Sci. 2013;125(12):575–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boehnert MU, Hilbig H, Armbruster FP. Relaxin as an additional protective substance in preserving and reperfusion solution for liver transplantation, shown in a model of isolated perfused rat liver. Ann N Y Acad Sci. 2005;1041:434–40.

    Article  CAS  PubMed  Google Scholar 

  • Boehnert MU, Armbruster FP, Hilbig H. Relaxin as a protective substance in preservation solutions for organ transplantation, as shown in an isolated perfused rat liver model. Transplant Proc. 2008;40(4):978–80.

    Article  CAS  PubMed  Google Scholar 

  • Boehnert MU, Armbruster FP, Hilbig H. Relaxin as a protective substance in the preserving solution for liver transplantation: spectrophotometric in vivo imaging of local oxygen supply in an isolated perfused rat liver model. Ann N Y Acad Sci. 2009;1160:320–1.

    Article  CAS  PubMed  Google Scholar 

  • Bogatcheva NV, Ferlin A, Feng S, Truong A, Gianesello L, Foresta C, et al. T222P mutation of the insulin-like 3 hormone receptor LGR8 is associated with testicular maldescent and hinders receptor expression on the cell surface membrane. Am J Physiol Endocrinol Metab. 2007;292:E138–44.

    Article  CAS  PubMed  Google Scholar 

  • Bogzil AH, Eardley R, Ashton N. Relaxin-induced changes in renal sodium excretion in the anesthetized male rat. Am J Phys Regul Integr Comp Phys. 2005;288(1):R322–8.

    CAS  Google Scholar 

  • Bohm M, Eschenhagen T, Gierschik P, Larisch K, Lensche H, Mende U, et al. Radioimmunochemical quantification of Gi alpha in right and left ventricles from patients with ischaemic and dilated cardiomyopathy and predominant left ventricular failure. J Mol Cell Cardiol. 1994;26(2):133–49.

    Article  CAS  PubMed  Google Scholar 

  • Bonner JS, Lantier L, Hocking KM, Kang L, Owolabi M, James FD, et al. Relaxin treatment reverses insulin resistance in mice fed a high-fat diet. Diabetes. 2013;62(9):3251–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Braddon SA. Relaxin-dependent adenosine 6′,5′-monophosphate concentration changes in the mouse pubic symphysis. Endocrinology. 1978;102(4):1292–9.

    Article  CAS  PubMed  Google Scholar 

  • Bruell S, Kong RC, Petrie EJ, Hoare B, Wade JD, Scott DJ, et al. Chimeric RXFP1 and RXFP2 receptors highlight the similar mechanism of activation utilizing their N-terminal low-density lipoprotein class A modules. Front Endocrinol. 2013;4:171.

    Article  Google Scholar 

  • Bullesbach EE, Schwabe C. Functional importance of the A chain loop in relaxin and insulin. J Biol Chem. 1994;269(18):13124–8.

    CAS  PubMed  Google Scholar 

  • Bullesbach EE, Schwabe C. Synthetic cross-links arrest the C-terminal region of the relaxin-like factor in an active conformation. Biochemistry. 2004;43(25):8021–8.

    Article  PubMed  CAS  Google Scholar 

  • Bullesbach EE, Schwabe C. The trap-like relaxin-binding site of LGR7. J Biol Chem. 2005a;280:14051–6.

    Article  PubMed  CAS  Google Scholar 

  • Bullesbach EE, Schwabe C. LGR8 signal activation by the relaxin-like factor. J Biol Chem. 2005b;280:14856–90.

    Google Scholar 

  • Carey RM. Cardiovascular and renal regulation by the angiotensin type 2 receptor: the AT2 receptor comes of age. Hypertension. 2005;45(5):840–4.

    Article  CAS  PubMed  Google Scholar 

  • Carrell DT, Peterson CM, Urry RL. The binding of recombinant human relaxin to human spermatozoa. Endocrinol Res. 1995;21:697–707.

    Article  CAS  Google Scholar 

  • Casten GG, Boucek RJ. Use of relaxin in the treatment of scleroderma. J Am Med Assoc. 1958;166(4):319–24.

    Article  CAS  PubMed  Google Scholar 

  • Chabre M, Deterre P, Antonny B. The apparent cooperativity of some GPCRs does not necessarily imply dimerization. Trends Pharmacol Sci. 2009;30(4):182–7.

    Article  CAS  PubMed  Google Scholar 

  • Chan SL, Cipolla MJ. Relaxin causes selective outward remodeling of brain parenchymal arterioles via activation of peroxisome proliferator-activated receptor-gamma. FASEB J. 2011;25(9):3229–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan LJ, Rosengren KJ, Layfield SL, Bathgate RA, Separovic F, Samuel CS, et al. 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. 2012;287(49):41152–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheah SH, Sherwood OD. Target tissues for relaxin in the rat: tissue distribution of injected 125I-labeled relaxin and tissue changes in adenosine 3′,5′-monophosphate levels after in vitro relaxin incubation. Endocrinology. 1980;106(4):1203–9.

    Article  CAS  PubMed  Google Scholar 

  • Chen GA, Huang JR, Tseng L. The effect of relaxin on cyclic adenosine 3′,5′-monophosphate concentrations in human endometrial glandular epithelial cells. Biol Reprod. 1988;39(3):519–25.

    Article  CAS  PubMed  Google Scholar 

  • Chen CZ, Southall N, Xiao J, Marugan JJ, Ferrer M, Hu X, et al. Identification of small-molecule agonists of human relaxin family receptor 1 (RXFP1) by using a homogenous cell-based cAMP assay. J Biomol Screen. 2013;18(6):670–7.

    Article  CAS  PubMed  Google Scholar 

  • Chow BS, Chew EG, Zhao C, Bathgate RA, Hewitson TD, Samuel CS. Relaxin signals through a RXFP1-pERK-nNOS-NO-cGMP-dependent pathway to up-regulate matrix metalloproteinases: the additional involvement of iNOS. PLoS One. 2012;7(8):e42714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chow BS, Kocan M, Bosnyak S, Sarwar M, Wigg B, Jones ES, et al. Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis. Kidney Int. 2014;86:75–85.

    Article  CAS  PubMed  Google Scholar 

  • Collino M, Rogazzo M, Pini A, Benetti E, Rosa AC, Chiazza F, et al. Acute treatment with relaxin protects the kidney against ischaemia/reperfusion injury. J Cell Mol Med. 2013;17(11):1494–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Conrad KP. Unveiling the vasodilatory actions and mechanisms of relaxin. Hypertension. 2010;56(1):2–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Conrad KP. Maternal vasodilation in pregnancy: the emerging role of relaxin. Am J Phys Regul Integr Comp Phys. 2011;301(2):R267–75.

    CAS  Google Scholar 

  • Conrad KP, Novak J. Emerging role of relaxin in renal and cardiovascular function. Am J Phys Regul Integr Comp Phys. 2004;287(2):R250–61.

    CAS  Google Scholar 

  • Conrad KP, Shroff SG. Effects of relaxin on arterial dilation, remodeling, and mechanical properties. Curr Hypertens Rep. 2011;13(6):409–20.

    Article  CAS  PubMed  Google Scholar 

  • Conrad KP, Debrah DO, Novak J, Danielson LA, Shroff SG. Relaxin modifies systemic arterial resistance and compliance in conscious, nonpregnant rats. Endocrinology. 2004;145(7):3289–96.

    Article  CAS  PubMed  Google Scholar 

  • Cosen-Binker LI, Binker MG, Cosen R, Negri G, Tiscornia O. Relaxin prevents the development of severe acute pancreatitis. World J Gastroenterol. 2006;12(10):1558–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Coulson CC, Thorp Jr JM, Mayer DC, Cefalo RC. Central hemodynamic effects of recombinant human relaxin in the isolated, perfused rat heart model. Obstet Gynecol. 1996;87(4):610–2.

    Article  CAS  PubMed  Google Scholar 

  • Danielson LA, Conrad KP. Time course and dose response of relaxin-mediated renal vasodilation, hyperfiltration, and changes in plasma osmolality in conscious rats. J Appl Physiol. 2003;95(4):1509–14.

    Article  CAS  PubMed  Google Scholar 

  • Danielson LA, Sherwood OD, Conrad KP. Relaxin is a potent renal vasodilator in conscious rats. J Clin Investig. 1999;103(4):525–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Danielson LA, Kercher LJ, Conrad KP. Impact of gender and endothelin on renal vasodilation and hyperfiltration induced by relaxin in conscious rats. Am J Phys Regul Integr Comp Phys. 2000;279(4):R1298–304.

    CAS  Google Scholar 

  • Davis D, Liu X, Segaloff DL. Identification of the sites of N-linked glycosylation on the follicle-stimulating hormone (FSH) receptor and assessment of their role in FSH receptor function. Mol Endocrinol. 1995;9(2):159–70.

    CAS  PubMed  Google Scholar 

  • Debrah DO, Conrad KP, Danielson LA, Shroff SG. Effects of relaxin on systemic arterial hemodynamics and mechanical properties in conscious rats: sex dependency and dose response. J Appl Physiol. 2005;98(3):1013–20.

    Article  CAS  PubMed  Google Scholar 

  • Debrah DO, Novak J, Matthews JE, Ramirez RJ, Shroff SG, Conrad KP. Relaxin is essential for systemic vasodilation and increased global arterial compliance during early pregnancy in conscious rats. Endocrinology. 2006;147(11):5126–31.

    Article  CAS  PubMed  Google Scholar 

  • Debrah DO, Debrah JE, Haney JL, McGuane JT, Sacks MS, Conrad KP, et al. Relaxin regulates vascular wall remodeling and passive mechanical properties in mice. J Appl Physiol. 2011;111(1):260–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Defer N, Best-Belpomme M, Hanoune J. Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. Am J Physiol Ren Physiol. 2000;279(3):F400–16.

    CAS  Google Scholar 

  • Del Borgo MP, Hughes RA, Bathgate RA, Lin F, Kawamura K, Wade JD. Analogs of insulin-like peptide 3 (INSL3) B-chain are LGR8 antagonists in vitro and in vivo. J Biol Chem. 2006;281(19):13068–74.

    Article  CAS  PubMed  Google Scholar 

  • Dschietzig T, Richter C, Bartsch C, Bohme C, Heinze D, Ott F, et al. Flow-induced pressure differentially regulates endothelin-1, urotensin II, adrenomedullin, and relaxin in pulmonary vascular endothelium. Biochem Biophys Res Commun. 2001a;289(1):245–51.

    Article  CAS  PubMed  Google Scholar 

  • Dschietzig T, Richter C, Bartsch C, Laule M, Armbruster FP, Baumann G, et al. The pregnancy hormone relaxin is a player in human heart failure. FASEB J. 2001b;15(12):2187–95.

    Article  CAS  PubMed  Google Scholar 

  • Dschietzig T, Bartsch C, Richter C, Laule M, Baumann G, Stangl K. Relaxin, a pregnancy hormone, is a functional endothelin-1 antagonist: attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-kappaB. Circ Res. 2003;92(1):32–40.

    Article  CAS  PubMed  Google Scholar 

  • Dschietzig T, Bartsch C, Stangl V, Baumann G, Stangl K. Identification of the pregnancy hormone relaxin as glucocorticoid receptor agonist. FASEB J. 2004;18(13):1536–8.

    CAS  PubMed  Google Scholar 

  • Dschietzig T, Bartsch C, Kinkel T, Baumann G, Stangl K. Myocardial relaxin counteracts hypertrophy in hypertensive rats. Ann N Y Acad Sci. 2005;1041:441–3.

    Article  CAS  PubMed  Google Scholar 

  • Dschietzig T, Bartsch C, Baumann G, Stangl K. RXFP1-inactive relaxin activates human glucocorticoid receptor: further investigations into the relaxin-GR pathway. Regul Pept. 2009a;154(1–3):77–84.

    Article  CAS  PubMed  Google Scholar 

  • Dschietzig T, Bartsch C, Wessler S, Baumann G, Stangl K. Autoregulation of human relaxin-2 gene expression critically involves relaxin and glucocorticoid receptor binding to glucocorticoid response half-sites in the relaxin-2 promoter. Regul Pept. 2009b;155(1–3):163–73.

    Article  CAS  PubMed  Google Scholar 

  • Dschietzig T, Teichman S, Unemori E, Wood S, Boehmer J, Richter C, et al. Intravenous recombinant human relaxin in compensated heart failure: a safety, tolerability, and pharmacodynamic trial. J Card Fail. 2009c;15(3):182–90.

    Article  CAS  PubMed  Google Scholar 

  • Dschietzig T, Alexiou K, Kinkel HT, Baumann G, Matschke K, Stangl K. The positive inotropic effect of relaxin-2 in human atrial myocardium is preserved in end-stage heart failure: role of G(i)-phosphoinositide-3 kinase signaling. J Card Fail. 2011;17(2):158–66.

    Article  CAS  PubMed  Google Scholar 

  • Dschietzig T, Brecht A, Bartsch C, Baumann G, Stangl K, Alexiou K. Relaxin improves TNF-alpha-induced endothelial dysfunction: the role of glucocorticoid receptor and phosphatidylinositol 3-kinase signalling. Cardiovasc Res. 2012;95(1):97–107.

    Article  CAS  PubMed  Google Scholar 

  • Egan CT, Herrick-Davis K, Teitler M. Creation of a constitutively activated state of the 5-Hydroxytryptamine2A receptor by site-directed mutagenesis: inverse agonist activity of antipsychotic drugs. J Pharmacol Exp Ther. 1998;286(1):85–90.

    CAS  PubMed  Google Scholar 

  • Eigenbrot C, Randal M, Quan C, Burnier J, O’Connell L, Rinderknecht E, et al. X-ray structure of human relaxin at 1.5 A. Comparison to insulin and implications for receptor binding determinants. J Mol Biol. 1991;221(1):15–21.

    CAS  PubMed  Google Scholar 

  • Erikson MS, Unemori EN. Relaxin clinical trials in systemic sclerosis. In: Tregear GW, Ivell R, Bathgate RA, Wade JD, editors. Relaxin 2000: proceedings of the third international conference on relaxin and related peptides. Amsterdam: Kluwer; 2001. p. 373–82.

    Chapter  Google Scholar 

  • Eschenhagen T, Mende U, Nose M, Schmitz W, Scholz H, Haverich A, et al. Increased messenger RNA level of the inhibitory G protein alpha subunit Gi alpha-2 in human end-stage heart failure. Circ Res. 1992;70(4):688–96.

    Article  CAS  PubMed  Google Scholar 

  • Familari M, Vu D, Parry LJ. Regulation of Rxfp2 (Lgr8) expression in the mouse fetal kidney by the transcription factor Pod1 (Tcf 21). Ann N Y Acad Sci. 2009;1160:317–9.

    Article  CAS  PubMed  Google Scholar 

  • Fan YH, Dong H, Pan Q, Cao YJ, Li H, Wang HC. Notch signaling may negatively regulate neonatal rat cardiac fibroblast-myofibroblast transformation. Physiol Res/Acad Sci Bohemoslovaca. 2011;60(5):739–48.

    CAS  Google Scholar 

  • Feng S, Agoulnik IU, Bogatcheva NV, Kamat AA, Kwabi-Addo B, Li R, et al. Relaxin promotes prostate cancer progression. Clin Cancer Res. 2007;13(6):1695–702.

    Article  CAS  PubMed  Google Scholar 

  • Feng S, Agoulnik IU, Truong A, Li Z, Creighton CJ, Kaftanovskaya EM, et al. Suppression of relaxin receptor RXFP1 decreases prostate cancer growth and metastasis. Endocr Relat Cancer. 2010;17(4):1021–33.

    Article  CAS  PubMed  Google Scholar 

  • Ferlin A, Pepe A, Gianesello L, Garolla A, Feng S, Giannini S, et al. Mutations in the insulin-like factor 3 receptor are associated with osteoporosis. J Bone Miner Res. 2008;23(5):683–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferlin A, Pepe A, Gianesello L, Garolla A, Feng S, Facciolli A, et al. New roles for INSL3 in adults. Ann N Y Acad Sci. 2009;1160:215–8.

    Article  CAS  PubMed  Google Scholar 

  • Ferlin A, Pepe A, Facciolli A, Gianesello L, Foresta C. Relaxin stimulates osteoclast differentiation and activation. Bone. 2010;46(2):504–13.

    Article  CAS  PubMed  Google Scholar 

  • Ferlin A, Menegazzo M, Gianesello L, Selice R, Foresta C. Effect of relaxin on human sperm functions and fertilizing ability. J Androl. 2012;33:474–82.

    Article  CAS  PubMed  Google Scholar 

  • Ferlin A, Selice R, Carraro U, Foresta C. Testicular function and bone metabolism – beyond testosterone. Nat Rev Endocrinol. 2013;9(9):548–54.

    Article  CAS  PubMed  Google Scholar 

  • Filonzi M, Cardoso LC, Pimenta MT, Queiroz DB, Avellar MC, Porto CS, et al. Relaxin family peptide receptors Rxfp1 and Rxfp2: mapping of the mRNA and protein distribution in the reproductive tract of the male rat. Reprod Biol Endocrinol. 2007;5:29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fisher C, MacLean M, Morecroft I, Seed A, Johnston F, Hillier C, et al. Is the pregnancy hormone relaxin also a vasodilator peptide secreted by the heart? Circulation. 2002;106(3):292–5.

    Article  CAS  PubMed  Google Scholar 

  • Fisher C, Berry C, Blue L, Morton JJ, McMurray J. N-terminal pro B type natriuretic peptide, but not the new putative cardiac hormone relaxin, predicts prognosis in patients with chronic heart failure. Heart. 2003;89(8):879–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Foresta C, Bettella A, Vinanzi C, Dabrilli P, Meriggiola MC, Garolla A, et al. A novel circulating hormone of testis origin in humans. J Clin Endocrinol Metab. 2004;89(12):5952–8.

    Article  CAS  PubMed  Google Scholar 

  • Fu P, Shen PJ, Zhao CX, Scott DJ, Samuel CS, Wade JD, et al. Leucine-rich repeat-containing G-protein-coupled receptor 8 in mature glomeruli of developing and adult rat kidney and inhibition by insulin-like peptide-3 of glomerular cell proliferation. J Endocrinol. 2006;189(2):397–408.

    Article  CAS  PubMed  Google Scholar 

  • Funato N, Ohyama K, Kuroda T, Nakamura M. Basic helix-loop-helix transcription factor epicardin/capsulin/Pod-1 suppresses differentiation by negative regulation of transcription. J Biol Chem. 2003;278(9):7486–93.

    Article  CAS  PubMed  Google Scholar 

  • Gambineri A, Patton L, De Iasio R, Palladoro F, Pagotto U, Pasquali R. Insulin-like factor 3: a new circulating hormone related to luteinizing hormone-dependent ovarian hyperandrogenism in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2007;92(6):2066–73.

    Article  CAS  PubMed  Google Scholar 

  • Gandley RE, Conrad KP, McLaughlin MK. Endothelin and nitric oxide mediate reduced myogenic reactivity of small renal arteries from pregnant rats. Am J Physiol Regul Integr Comp Physiol. 2001;280(1):R1–7.

    CAS  PubMed  Google Scholar 

  • Garber SL, Mirochnik Y, Brecklin CS, Unemori EN, Singh AK, Slobodskoy L, et al. Relaxin decreases renal interstitial fibrosis and slows progression of renal disease. Kidney Int. 2001;59(3):876–82.

    Article  CAS  PubMed  Google Scholar 

  • Gelman S. Venous function and central venous pressure: a physiologic story. Anesthesiology. 2008;108(4):735–48.

    Article  PubMed  Google Scholar 

  • Glister C, Satchell L, Bathgate RA, Wade JD, Dai Y, Ivell R, et al. Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production. Proc Natl Acad Sci U S A. 2013;110(15):E1426–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glogowska A, Kunanuvat U, Stetefeld J, Patel TR, Thanasupawat T, Krcek J, et al. C1q-tumour necrosis factor-related protein 8 (CTRP8) is a novel interaction partner of relaxin receptor RXFP1 in human brain cancer cells. J Pathol. 2013;231(4):466–79.

    Article  CAS  PubMed  Google Scholar 

  • Gooi JH, Richardson ML, Jelinic M, Girling JE, Wlodek ME, Tare M, et al. Enhanced uterine artery stiffness in aged pregnant relaxin mutant mice is reversed with exogenous relaxin treatment. Biol Reprod. 2013;89(1):18.

    Article  PubMed  CAS  Google Scholar 

  • Gorlov IP, Kamat A, Bogatcheva NV, Jones E, Lamb DJ, Truong A, et al. Mutations of the GREAT gene cause cryptorchidism. Hum Mol Genet. 2002;11(19):2309–18.

    Article  CAS  PubMed  Google Scholar 

  • Haley J, Hudson P, Scanlon D, John M, Cronk M, Shine J, et al. Porcine relaxin: molecular cloning and cDNA structure. DNA. 1982;1(2):155–62.

    Article  CAS  PubMed  Google Scholar 

  • Halls ML, Cooper DM. Sub-picomolar relaxin signalling by a pre-assembled RXFP1, AKAP79, AC2, beta-arrestin 2, PDE4D3 complex. EMBO J. 2010;29(16):2772–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Halls ML, Bond CP, Sudo S, Kumagai J, Ferraro T, Layfield S, et al. 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. 2005;313(2):677–87.

    Article  CAS  PubMed  Google Scholar 

  • Halls ML, Bathgate RA, Summers RJ. Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP signaling by distinct mechanisms. Mol Pharmacol. 2006;70(1):214–26.

    CAS  PubMed  Google Scholar 

  • Halls ML, van der Westhuizen ET, Bathgate RA, Summers RJ. Relaxin family peptide receptors – former orphans reunite with their parent ligands to activate multiple signalling pathways. Br J Pharmacol. 2007a;150(6):677–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Halls ML, Bathgate RA, Summers RJ. Comparison of signaling pathways activated by the relaxin family peptide receptors, RXFP1 and RXFP2, using reporter genes. J Pharmacol Exp Ther. 2007b;320(1):281–90.

    Article  CAS  PubMed  Google Scholar 

  • Halls ML, van der Westhuizen ET, Wade JD, Evans BA, Bathgate RA, Summers RJ. Relaxin family peptide receptor (RXFP1) coupling to G(alpha)i3 involves the C-terminal Arg752 and localization within membrane raft microdomains. Mol Pharmacol. 2009a;75(2):415–28.

    Article  CAS  PubMed  Google Scholar 

  • Halls ML, Hewitson TD, Moore XL, Du XJ, Bathgate RA, Summers RJ. Relaxin activates multiple cAMP signaling pathway profiles in different target cells. Ann N Y Acad Sci. 2009b;1160:108–11.

    Article  CAS  PubMed  Google Scholar 

  • Halls ML, Bathgate RA, Sutton SW, Dschietzig TB, Summers RJ. International Union of Basic and Clinical Pharmacology. XCV. Recent advances in the understanding of the pharmacology and biological roles of relaxin family peptide receptors 1-4, the receptors for relaxin family peptides. Pharmacol Rev. 2015;67(2):389–440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hartley BJ, Scott DJ, Callander GE, Wilkinson TN, Ganella DE, Kong CK, et al. Resolving the unconventional mechanisms underlying RXFP1 and RXFP2 receptor function. Ann N Y Acad Sci. 2009;1160:67–73.

    Article  CAS  PubMed  Google Scholar 

  • Heeg MHJ, Koziolek MJ, Vasko R, Schaefer L, Sharma K, Muller GA, et al. The antifibrotic effects of relaxin in human renal fibroblasts are mediated in part by inhibition of the Smad2 pathway. Kidney Int. 2005;68(1):96–109.

    Article  CAS  PubMed  Google Scholar 

  • Heng K, Ivell R, Wagaarachchi P, Anand-Ivell R. Relaxin signalling in primary cultures of human myometrial cells. Mol Hum Reprod. 2008;14(10):603–11.

    Article  CAS  PubMed  Google Scholar 

  • Herrick-Davis K, Egan CT, Teitler M. Activating mutations of the serotonin 5-HT2C receptor. J Neurochem. 1997;69(3):1138–44.

    Article  CAS  PubMed  Google Scholar 

  • Hisaw FL. Experimental relaxation of the pubic ligament of the guinea pig. Proc Soc Exp Biol Med. 1926;23:661–3.

    Article  Google Scholar 

  • Hombach-Klonisch S, Hoang-Vu C, Kehlen A, Hinze R, Holzhausen HJ, Weber E, et al. INSL-3 is expressed in human hyperplastic and neoplastic thyrocytes. Int J Oncol. 2003;22(5):993–1001.

    CAS  PubMed  Google Scholar 

  • Hombach-Klonisch S, Bialek J, Trojanowicz B, Weber E, Holzhausen H-J, Silvertown JD, et al. Relaxin enhances the oncogenic potential of human thyroid carcinoma cells. Am J Pathol. 2006;169(2):617–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hombach-Klonisch S, Bialek J, Radestock Y, Truong A, Agoulnik AI, Fiebig B, et al. INSL3 has tumor-promoting activity in thyroid cancer. Int J Cancer. 2010;127(3):521–31.

    Article  CAS  PubMed  Google Scholar 

  • Hopkins EJ, Layfield S, Ferraro T, Bathgate RA, Gooley PR. The NMR solution structure of the relaxin (RXFP1) receptor lipoprotein receptor class A module and identification of key residues in the N-terminal region of the module that mediate receptor activation. J Biol Chem. 2007;282(6):4172–84.

    Article  CAS  PubMed  Google Scholar 

  • Horton JS, Yamamoto SY, Bryant-Greenwood GD. Relaxin modulates proinflammatory cytokine secretion from human decidual macrophages. Biol Reprod. 2011;85(4):788–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hossain MA, Rosengren KJ, Haugaard-Jonsson LM, Zhang S, Layfield S, Ferraro T, et al. 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. 2008;283(25):17287–97.

    Article  CAS  PubMed  Google Scholar 

  • Hossain MA, Rosengren KJ, Samuel CS, Shabanpoor F, Chan LJ, Bathgate RA, et al. The minimal active structure of human relaxin-2. J Biol Chem. 2011;286(43):37555–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hsu SYT. New insights into the evolution of the relaxin – LGR signaling system. Trends Endocrinol Metab. 2003;14(7):303–9.

    Article  CAS  PubMed  Google Scholar 

  • Hsu SY, Kudo M, Chen T, Nakabayashi K, Bhalla A, van der Spek PJ, et al. The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol Endocrinol. 2000;14(8):1257–71.

    Article  CAS  PubMed  Google Scholar 

  • Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, et al. Activation of orphan receptors by the hormone relaxin. Science. 2002;295(5555):671–4.

    Article  CAS  PubMed  Google Scholar 

  • Hu X, Myhr C, Huang Z, Xiao J, Barnaeva E, Ho BA, et al. Structural insights into the activation of human relaxin family peptide receptor 1 by small-molecule agonists. Biochemistry. 2016;55(12):1772–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang Z, Myhr C, Bathgate RA, Ho BA, Bueno A, Hu X, et al. Activation of relaxin family receptor 1 from different mammalian species by relaxin peptide and small-molecule agonist ML290. Front Endocrinol. 2015;6:128.

    Article  Google Scholar 

  • Hudson P, Haley J, Cronk M, Shine J, Niall H. Molecular cloning and characterization of cDNA sequences coding for rat relaxin. Nature. 1981;291(5811):127–31.

    Article  CAS  PubMed  Google Scholar 

  • Hudson P, Haley J, John M, Cronk M, Crawford R, Haralambidis J, et al. Structure of a genomic clone encoding biologically active human relaxin. Nature. 1983;301(5901):628–31.

    Article  CAS  PubMed  Google Scholar 

  • Hudson P, John M, Crawford R, Haralambidis J, Scanlon D, Gorman J, et al. Relaxin gene expression in human ovaries and the predicted structure of a human preprorelaxin by analysis of cDNA clones. EMBO J. 1984;3(10):2333–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ivell R, Anand-Ivell R. Biology of insulin-like factor 3 in human reproduction. Hum Reprod Update. 2009;15(4):463–76.

    Article  CAS  PubMed  Google Scholar 

  • Ivell R, Bathgate RA. Reproductive biology of the relaxin-like factor (RLF/INSL3). Biol Reprod. 2002;67(3):699–705.

    Article  CAS  PubMed  Google Scholar 

  • Ivell R, Balvers M, Pohnke Y, Telgmann R, Bartsch O, Milde-Langosch K, et al. Immunoexpression of the relaxin receptor LGR7 in breast and uterine tissues of humans and primates. Reprod Biol Endocrinol. 2003;1:114.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ivell R, Heng K, Anand-Ivell R. Insulin-like factor 3 and the HPG axis in the male. Front Endocrinol. 2014;5:6.

    Article  Google Scholar 

  • James R, Niall H, Kwok S, Bryand-Greenwood G. Primary structure of porcine relaxin: homology with insulin and related growth factors. Nature. 1977;267(5611):544–6.

    Article  CAS  PubMed  Google Scholar 

  • Jarrett Jd, Ballejo G, Saleem TH, Tsibris JC, Spellacy WN. The effect of prolactin and relaxin on insulin binding by adipocytes from pregnant women. Am J Obstet Gynecol. 1984;149(3):250–5.

    Google Scholar 

  • Jelinic M, Leo CH, Post Uiterweer ED, Sandow SL, Gooi JH, Wlodek ME, et al. Localization of relaxin receptors in arteries and veins, and region-specific increases in compliance and bradykinin-mediated relaxation after in vivo serelaxin treatment. FASEB J. 2014;28(1):275–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jeyabalan A, Novak J, Danielson LA, Kerchner LJ, Opett SL, Conrad KP. Essential role for vascular gelatinase activity in relaxin-induced renal vasodilation, hyperfiltration, and reduced myogenic reactivity of small arteries. Circ Res. 2003;93(12):1249–57.

    Article  CAS  PubMed  Google Scholar 

  • Jeyabalan A, Kerchner LJ, Fisher MC, McGuane JT, Doty KD, Conrad KP. Matrix metalloproteinase-2 activity, protein, mRNA, and tissue inhibitors in small arteries from pregnant and relaxin-treated nonpregnant rats. J Appl Physiol. 2006;100(6):1955–63.

    Article  CAS  PubMed  Google Scholar 

  • John MJ, Borjesson BW, Walsh JR, Niall HD. Limited sequence homology between porcine and rat relaxins: implications for physiological studies. Endocrinology. 1981;108(2):726–9.

    Article  CAS  PubMed  Google Scholar 

  • Johnson MR, Abdalla H, Allman AC, Wren ME, Kirkland A, Lightman SL. Relaxin levels in ovum donation pregnancies. Fertil Steril. 1991;56(1):59–61.

    Article  CAS  PubMed  Google Scholar 

  • Johnson MR, Brooks AA, Steer PJ. The role of relaxin in the pregnancy associated reduction in plasma osmolality. Hum Reprod. 1996;11(5):1105–8.

    Article  CAS  PubMed  Google Scholar 

  • Johnston SE, Gratten J, Berenos C, Pilkington JG, Clutton-Brock TH, Pemberton JM, et al. Life history trade-offs at a single locus maintain sexually selected genetic variation. Nature. 2013;502(7469):93–5.

    Article  CAS  PubMed  Google Scholar 

  • Jones ES, Vinh A, McCarthy CA, Gaspari TA, Widdop RE. AT2 receptors: functional relevance in cardiovascular disease. Pharmacol Ther. 2008;120(3):292–316.

    Article  CAS  PubMed  Google Scholar 

  • Kakouris H, Eddie LW, Summers RJ. Cardiac effects of relaxin in rats. Lancet. 1992;339(8801):1076–8.

    Article  CAS  PubMed  Google Scholar 

  • Kamat AA, Feng S, Bogatcheva NV, Truong A, Bishop CE, Agoulnik AI. Genetic targeting of relaxin and insulin-like factor 3 receptors in mice. Endocrinology. 2004;145(10):4712–20.

    Article  CAS  PubMed  Google Scholar 

  • Kamat AA, Feng S, Agoulnik IU, Kheradmand F, Bogatcheva NV, Coffey D, et al. The role of relaxin in endometrial cancer. Cancer Biol Ther. 2006;5(1):71–7.

    Article  CAS  PubMed  Google Scholar 

  • Kawamura K, Kumagai J, Sudo S, Chun SY, Pisarska M, Morita H, et al. Paracrine regulation of mammalian oocyte maturation and male germ cell survival. Proc Natl Acad Sci U S A. 2004;101(19):7323–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kern A, Agoulnik AI, Bryant-Greenwood GD. The low-density lipoprotein class A module of the relaxin receptor (leucine-rich repeat containing G-protein coupled receptor 7): its role in signaling and trafficking to the cell membrane. Endocrinology. 2007;148(3):1181–94.

    Article  CAS  PubMed  Google Scholar 

  • Kern A, Hubbard D, Amano A, Bryant-Greenwood GD. Cloning, expression, and functional characterization of relaxin receptor (leucine-rich repeat-containing g protein-coupled receptor 7) splice variants from human fetal membranes. Endocrinology. 2008;149(3):1277–94.

    Article  CAS  PubMed  Google Scholar 

  • Khanna D, Clements PJ, Furst DE, Korn JH, Ellman M, Rothfield N, et al. Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2009;60(4):1102–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kjelsberg MA, Cotecchia S, Ostrowski J, Caron MG, Lefkowitz RJ. Constitutive activation of the alpha 1B-adrenergic receptor by all amino acid substitutions at a single site. Evidence for a region which constrains receptor activation. J Biol Chem. 1992;267(3):1430–3.

    CAS  PubMed  Google Scholar 

  • Klonisch T, Muller-Huesmann H, Riedel M, Kehlen A, Bialek J, Radestock Y, et al. INSL3 in the benign hyperplastic and neoplastic human prostate gland. Int J Oncol. 2005;27(2):307–15.

    CAS  PubMed  Google Scholar 

  • Kohsaka T, Min G, Lukas G, Trupin S, Campbell ET, Sherwood OD. Identification of specific relaxin-binding cells in the human female. Biol Reprod. 1998;59(4):991–9.

    Article  CAS  PubMed  Google Scholar 

  • Kompa AR, Samuel CS, Summers RJ. Inotropic responses to human gene 2 (B29) relaxin in a rat model of myocardial infarction (MI): effect of pertussis toxin. Br J Pharmacol. 2002;137(5):710–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kong RC, Shilling PJ, Lobb DK, Gooley PR, Bathgate RA. Membrane receptors: structure and function of the relaxin family peptide receptors. Mol Cell Endocrinol. 2010;320(1–2):1–15.

    Article  CAS  PubMed  Google Scholar 

  • Kong RC, Petrie EJ, Mohanty B, Ling J, Lee JC, Gooley PR, et al. The relaxin receptor (RXFP1) utilises hydrophobic moieties on a signalling surface of its N-terminal low density lipoprotein class A module to mediate receptor activation. J Biol Chem. 2013;288:28138–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krajnc-Franken MA, van Disseldorp AJ, Koenders JE, Mosselman S, van Duin M, Gossen JA. Impaired nipple development and parturition in LGR7 knockout mice. Mol Cell Biol. 2004;24(2):687–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumagai J, Hsu SY, Matsumi H, Roh JS, Fu P, Wade JD, et al. INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. J Biol Chem. 2002;277(35):31283–6.

    Article  CAS  PubMed  Google Scholar 

  • Kuznetsova L, Plesneva S, Derjabina N, Omeljaniuk E, Pertseva M. On the mechanism of relaxin action: the involvement of adenylyl cyclase signalling system. Regul Pept. 1999;80(1–2):33–9.

    Article  CAS  PubMed  Google Scholar 

  • Lee AB, Hwang JJ, Haab LM, Fields PA, Sherwood OD. Monoclonal antibodies specific for rat relaxin. VI. Passive immunization with monoclonal antibodies throughout the second half of pregnancy disrupts histological changes associated with cervical softening at parturition in rats. Endocrinology. 1992;130(4):2386–91.

    CAS  PubMed  Google Scholar 

  • Lekgabe ED, Kiriazis H, Zhao C, Xu Q, Moore XL, Su Y, et al. Relaxin reverses cardiac and renal fibrosis in spontaneously hypertensive rats. Hypertension. 2005;46(2):412–8.

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Brookes ZL, Kaufman S. Acute and chronic effects of relaxin on vasoactivity, myogenic reactivity and compliance of the rat mesenteric arterial and venous vasculature. Regul Pept. 2005;132(1–3):41–6.

    Article  CAS  PubMed  Google Scholar 

  • Longo M, Jain V, Vedernikov YP, Garfield RE, Saade GR. Effects of recombinant human relaxin on pregnant rat uterine artery and myometrium in vitro. Am J Obstet Gynecol 2003;188(6):1468–1474; discussion 74–6.

    Google Scholar 

  • Ma S, Roozendaal B, Burazin TC, Tregear GW, McGaugh JL, Gundlach AL. Relaxin receptor activation in the basolateral amygdala impairs memory consolidation. Eur J Neurosci. 2005;22(8):2117–22.

    Article  PubMed  Google Scholar 

  • Ma JF, Liu L, Yang WJ, Zang LN, Xi YM. RNAi-mediated knockdown of relaxin decreases in vitro proliferation and invasiveness of osteosarcoma MG-63 cells by inhibition of MMP-9. Eur Rev Med Pharmacol Sci. 2013a;17(8):1102–9.

    PubMed  Google Scholar 

  • Ma JF, Von Kalle M, Plautz Q, MX F, Singh L, Wang L. Relaxin promotes in vitro tumour growth, invasion and angiogenesis of human Saos-2 osteosarcoma cells by AKT/VEGF pathway. Eur Rev Med Pharmacol Sci. 2013b;17(10):1345–50.

    PubMed  Google Scholar 

  • Masini E, Bani D, Bello MG, Bigazzi M, Mannaioni PF, Sacchi TB. Relaxin counteracts myocardial damage induced by ischemia-reperfusion in isolated guinea pig hearts: evidence for an involvement of nitric oxide. Endocrinology. 1997;138(11):4713–20.

    Article  CAS  PubMed  Google Scholar 

  • Massicotte G, Parent A, St-Louis J. Blunted responses to vasoconstrictors in mesenteric vasculature but not in portal vein of spontaneously hypertensive rats treated with relaxin. Proc Soc Exp Biol Med. 1989;190(3):254–9.

    Article  CAS  PubMed  Google Scholar 

  • Mathieu MN, Wade JD, Tregear GW, Bond CP, Summers RJ, Catimel B, et al. Synthesis, conformational studies and biological activity of N(alpha)- mono-biotinylated rat relaxin. J Pept Res. 2001;57(5):374–82.

    Article  CAS  PubMed  Google Scholar 

  • Matsubara H. Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal diseases. Circ Res. 1998;83(12):1182–91.

    Article  CAS  PubMed  Google Scholar 

  • McDonald GA, Sarkar P, Rennke H, Unemori E, Kalluri R, Sukhatme VP. Relaxin increases ubiquitin-dependent degradation of fibronectin in vitro and ameliorates renal fibrosis in vivo. Am J Physiol Ren Physiol. 2003;285(1):F59–67.

    Article  CAS  Google Scholar 

  • McGowan BM, Minnion JS, Murphy KG, White NE, Roy D, Stanley SA, et al. Central and peripheral administration of human relaxin-2 to adult male rats inhibits food intake. Diabetes Obes Metab. 2010;12(12):1090–6.

    Article  CAS  PubMed  Google Scholar 

  • McGuane JT, Debrah JE, Sautina L, Jarajapu YP, Novak J, Rubin JP, et al. Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide. Endocrinology. 2011;152(7):2786–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Millar LK, Reiny R, Yamamoto SY, Okazaki K, Webster L, Bryant-Greenwood GD. Relaxin causes proliferation of human amniotic epithelium by stimulation of insulin-like growth factor-II. Am J Obstet Gynecol. 2003;188(1):234–41.

    Article  CAS  PubMed  Google Scholar 

  • Mookerjee I, Hewitson TD, Halls ML, Summers RJ, Mathai ML, Bathgate RA, et al. Relaxin inhibits renal myofibroblast differentiation via RXFP1, the nitric oxide pathway, and Smad2. FASEB J. 2009;23(4):1219–29.

    Article  CAS  PubMed  Google Scholar 

  • Moore XL, Tan SL, Lo CY, Fang L, Su YD, Gao XM, et al. Relaxin antagonizes hypertrophy and apoptosis in neonatal rat cardiomyocytes. Endocrinology. 2007;148:1582–9.

    Article  CAS  PubMed  Google Scholar 

  • Nef S, Parada LF. Cryptorchidism in mice mutant for INSL3. Nat Genet. 1999;22(3):295–9.

    Article  CAS  PubMed  Google Scholar 

  • Nguyen BT, Dessauer CW. Relaxin stimulates protein kinase C z translocation: requirement for cyclic adenosine 3′,5′-monophosphate production. Mol Endocrinol. 2005;19(4):1012–23.

    Article  CAS  PubMed  Google Scholar 

  • Nguyen BT, Yang L, Sanborn BM, Dessauer CW. Phosphoinositide 3-kinase activity is required for biphasic stimulation of cyclic adenosine 3′,5′-monophosphate by relaxin. Mol Endocrinol. 2003;17(6):1075–84.

    Article  CAS  PubMed  Google Scholar 

  • Nistri S, Bani D. Relaxin receptors and nitric oxide synthases: search for the missing link. Reprod Biol Endocrinol. 2003;1(1):5.

    Article  PubMed  PubMed Central  Google Scholar 

  • Novak J, Danielson LA, Kerchner LJ, Sherwood OD, Ramirez RJ, Moalli PA, et al. Relaxin is essential for renal vasodilation during pregnancy in conscious rats. J Clin Invest. 2001;107(11):1469–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Novak J, Ramirez RJ, Gandley RE, Sherwood OD, Conrad KP. Myogenic reactivity is reduced in small renal arteries isolated from relaxin-treated rats. Am J Phys Regul Integr Comp Phys. 2002;283(2):R349–55.

    CAS  Google Scholar 

  • Novak J, Parry LJ, Matthews JE, Kerchner LJ, Indovina K, Hanley-Yanez K, et al. Evidence for local relaxin ligand-receptor expression and function in arteries. FASEB J. 2006;20(13):2352–62.

    Article  CAS  PubMed  Google Scholar 

  • O’Byrne EM, Carriere BT, Sorensen L, Segaloff A, Schwabe C, Steinetz BG. Plasma immunoreactive relaxin levels in pregnant and nonpregnant women. J Clin Endocrinol Metab. 1978;47(5):1106–10.

    Article  PubMed  Google Scholar 

  • Olefsky JM, Saekow M, Kroc RL. Potentiation of insulin binding and insulin action by purified porcine relaxin. Ann N Y Acad Sci. 1982;380(200):200–16.

    Article  CAS  PubMed  Google Scholar 

  • Osheroff PL, Ho WH. Expression of relaxin mRNA and relaxin receptors in postnatal and adult rat brains and hearts. Localization and developmental patterns. J Biol Chem. 1993;268(20):15193–9.

    CAS  PubMed  Google Scholar 

  • Osheroff PL, Cronin MJ, Lofgren JA. Relaxin binding in the rat heart atrium. Proc Natl Acad Sci U S A. 1992;89:2384–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Overbeek PA, Gorlov IP, Sutherland RW, Houston JB, Harrison WR, Boettger-Tong HL, et al. A transgenic insertion causing cryptorchidism in mice. Genesis. 2001;30(1):26–35.

    Article  CAS  PubMed  Google Scholar 

  • Palejwala S, Stein D, Wojtczuk A, Weiss G, Goldsmith LT. Demonstration of a relaxin receptor and relaxin-stimulated tyrosine phosphorylation in human lower uterine segment fibroblasts. Endocrinology. 1998;139(3):1208–12.

    Article  CAS  PubMed  Google Scholar 

  • Pan HZ, Dong AB, Wang L, Tan SS, Yang Q, Tong XY, et al. Significance of relaxin-2 expression in hepatocellular carcinoma: relation with clinicopathological parameters. Eur Rev Med Pharmacol Sci. 2013;17(8):1095–101.

    PubMed  Google Scholar 

  • Parikh A, Patel D, McTiernan CF, Xiang W, Haney J, Yang L, et al. Relaxin suppresses atrial fibrillation by reversing fibrosis and myocyte hypertrophy and increasing conduction velocity and sodium current in spontaneously hypertensive rat hearts. Circ Res. 2013;113(3):313–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park JI, Semyonov J, Yi W, Chang CL, Hsu SY. Regulation of receptor signaling by relaxin A chain motifs: derivation of pan-specific and LGR7-specific human relaxin analogs. J Biol Chem. 2008;283(46):32099–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pathirana IN, Kawate N, Bullesbach EE, Takahashi M, Hatoya S, Inaba T, et al. Insulin-like peptide 3 stimulates testosterone secretion in mouse Leydig cells via cAMP pathway. Regul Pept. 2012;178(1–3):102–6.

    Article  CAS  PubMed  Google Scholar 

  • Pepe A, Ferlin A, Gianesello L, Facciolli A, Agoulnik AI, Foresta C. INSL3 plays a role in the balance between bone formation and resorption. Ann N Y Acad Sci. 2009;1160:219–20.

    Article  PubMed  Google Scholar 

  • Perna AM, Masini E, Nistri S, Briganti V, Chiappini L, Stefano P, et al. Novel drug development opportunity for relaxin in acute myocardial infarction: evidences from a swine model. FASEB J. 2005;19(11):1525–7.

    CAS  PubMed  Google Scholar 

  • Petersen LK, Svane D, Uldbjerg N, Forman A. Effects of human relaxin on isolated rat and human myometrium and uteroplacental arteries. Obstet Gynecol. 1991;78(5):757–62.

    CAS  PubMed  Google Scholar 

  • Piedras-Renteria ES, Sherwood OD, Best PM. Effects of relaxin on rat atrial myocytes. II. Increased calcium influx derived from action potential prolongation. Am J Phys. 1997a;272(4 Pt 2):H1798–803.

    CAS  Google Scholar 

  • Piedras-Renteria ES, Sherwood OD, Best PM. Effects of relaxin on rat atrial myocytes. I. Inhibition of I(to) via PKA-dependent phosphorylation. Am J Phys. 1997b;272(4 Pt 2):H1791–7.

    CAS  Google Scholar 

  • Pietila EM, Tuusa JT, Apaja PM, Aatsinki JT, Hakalahti AE, Rajaniemi HJ, et al. Inefficient maturation of the rat luteinizing hormone receptor: a putative way to regulate receptor numbers at the cell surface. J Biol Chem. 2005;280(28):26622–9.

    Article  PubMed  CAS  Google Scholar 

  • Pini A, Shemesh R, Samuel CS, Bathgate RA, Zauberman A, Hermesh C, et al. Prevention of bleomycin-induced pulmonary fibrosis by a novel antifibrotic peptide with relaxin-like activity. J Pharmacol Exp Ther. 2010;335(3):589–99.

    Article  CAS  PubMed  Google Scholar 

  • Pusch W, Balvers M, Ivell R. Molecular cloning and expression of the relaxin-like factor from the mouse testis. Endocrinology. 1996;137(7):3009–13.

    Article  CAS  PubMed  Google Scholar 

  • Quaggin SE, Schwartz L, Cui S, Igarashi P, Deimling J, Post M, et al. The basic-helix-loop-helix protein pod1 is critically important for kidney and lung organogenesis. Development. 1999;126(24):5771–83.

    CAS  PubMed  Google Scholar 

  • Quintana J, Hipkin RW, Ascoli M. A polyclonal antibody to a synthetic peptide derived from the rat follicle-stimulating hormone receptor reveals the recombinant receptor as a 74-kilodalton protein. Endocrinology. 1993;133(5):2098–104.

    Article  CAS  PubMed  Google Scholar 

  • Radestock Y, Hoang-Vu C, Hombach-Klonisch S. Relaxin reduces xenograft tumour growth of human MDA-MB-231 breast cancer cells. Breast Cancer Res. 2008;10(4):R71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ren Q, Kurose H, Lefkowitz RJ, Cotecchia S. Constitutively active mutants of the alpha 2-adrenergic receptor. J Biol Chem. 1993;268(22):16483–7.

    CAS  PubMed  Google Scholar 

  • Ren P, Yu ZT, Xiu L, Wang M, Liu HM. Elevated serum levels of human relaxin-2 in patients with esophageal squamous cell carcinoma. World J Gastroenterol. 2013;19(15):2412–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosengren KJ, Zhang S, Lin F, Daly NL, Scott DJ, Hughes RA, et al. Solution structure and characterization of the LGR8 receptor binding surface of insulin-like peptide 3. J Biol Chem. 2006;281(38):28287–95.

    Article  CAS  PubMed  Google Scholar 

  • Sadana R, Dessauer CW. Physiological roles for G protein-regulated adenylyl cyclase isoforms: insights from knockout and overexpression studies. Neurosignals. 2009;17(1):5–22.

    Article  CAS  PubMed  Google Scholar 

  • Samuel CS, Zhao C, Bathgate RA, Bond CP, Burton MD, Parry LJ, et al. Relaxin deficiency in mice is associated with an age-related progression of pulmonary fibrosis. FASEB J. 2003;17(1):121–3.

    CAS  PubMed  Google Scholar 

  • Samuel CS, Unemori EN, Mookerjee I, Bathgate RA, Layfield SL, Mak J, et al. Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo. Endocrinology. 2004a;145(9):4125–33.

    Article  CAS  PubMed  Google Scholar 

  • Samuel CS, Zhao C, Bond CP, Hewitson TD, Amento EP, Summers RJ. Relaxin-1-deficient mice develop an age-related progression of renal fibrosis. Kidney Int. 2004b;65(6):2054–64.

    Article  CAS  PubMed  Google Scholar 

  • Samuel CS, Zhao C, Bathgate RA, Du XJ, Summers RJ, Amento EP, et al. The relaxin gene-knockout mouse: a model of progressive fibrosis. Ann N Y Acad Sci. 2005;1041:173–81.

    Article  CAS  PubMed  Google Scholar 

  • Samuel CS, Royce SG, Burton MD, Zhao C, Tregear GW, Tang ML. Relaxin plays an important role in the regulation of airway structure and function. Endocrinology. 2007;148(9):4259–66.

    Article  CAS  PubMed  Google Scholar 

  • Samuel CS, Hewitson TD, Zhang Y, Kelly DJ. Relaxin ameliorates fibrosis in experimental diabetic cardiomyopathy. Endocrinology. 2008;149(7):3286–93.

    Article  CAS  PubMed  Google Scholar 

  • Samuel CS, Cendrawan S, Gao XM, Ming Z, Zhao C, Kiriazis H, et al. Relaxin remodels fibrotic healing following myocardial infarction. Lab Investig. 2011;91(5):675–90.

    Article  CAS  PubMed  Google Scholar 

  • Sanborn BM, Kuo HS, Weisbrodt NW, Sherwood OD. The interaction of relaxin with the rat uterus. I. Effect on cyclic nucleotide levels and spontaneous contractile activity. Endocrinology. 1980;106(4):1210–5.

    Article  CAS  PubMed  Google Scholar 

  • Sarwar M, Samuel CS, Bathgate RA, Stewart DR, Summers RJ. Serelaxin-mediated signal transduction in human vascular cells: bell-shaped concentration-response curves reflect differential coupling to G proteins. Br J Pharmacol. 2015;172:1005–19.

    Article  CAS  PubMed  Google Scholar 

  • Sarwar M, Samuel CS, Bathgate RA, Stewart DR, Summers RJ. Enhanced serelaxin signalling in co-cultures of human primary endothelial and smooth muscle cells. Br J Pharmacol. 2016;173:484–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Savoia C, Ebrahimian T, He Y, Gratton JP, Schiffrin EL, Touyz RM. Angiotensin II/AT2 receptor-induced vasodilation in stroke-prone spontaneously hypertensive rats involves nitric oxide and cGMP-dependent protein kinase. J Hypertens. 2006;24(12):2417–22.

    Article  CAS  PubMed  Google Scholar 

  • Schondorf T, Lubben G, Hoopmann M, Borchert M, Forst T, Hohberg C, et al. Relaxin expression correlates significantly with serum fibrinogen variation in response to antidiabetic treatment in women with type 2 diabetes mellitus. Gynecol Endocrinol. 2007;23(6):356–60.

    Article  PubMed  CAS  Google Scholar 

  • Schwabe C, Bullesbach EE. Relaxin: structures, functions, promises, and nonevolution. FASEB J. 1994;8:1152–60.

    CAS  PubMed  Google Scholar 

  • Schwabe C, McDonald JK. Primary structure of the B-chain of porcine relaxin. Biochem Biophys Res Commun. 1977;75(2):503–10.

    Article  CAS  PubMed  Google Scholar 

  • Scott DJ, Layfield S, Riesewijk A, Morita H, Tregear GW, Bathgate RA. Characterization of the mouse and rat relaxin receptors. Ann N Y Acad Sci. 2005a;1041:8–12.

    Article  CAS  PubMed  Google Scholar 

  • Scott DJ, Tregear GW, Bathgate RA. LGR7-truncate is a splice variant of the relaxin receptor LGR7 and is a relaxin antagonist in vitro. Ann N Y Acad Sci. 2005b;1041:22–6.

    Article  CAS  PubMed  Google Scholar 

  • Scott DJ, Fu P, Shen PJ, Gundlach A, Layfield S, Riesewijk A, et al. Characterization of the rat INSL3 receptor. Ann N Y Acad Sci. 2005c;1041:13–6.

    Article  CAS  PubMed  Google Scholar 

  • Scott DJ, Layfield S, Yan Y, Sudo S, Hsueh AJ, Tregear GW, et al. Characterization of novel splice variants of LGR7 and LGR8 reveals that receptor signaling is mediated by their unique LDLa modules. J Biol Chem. 2006;281:34942–54.

    Article  CAS  PubMed  Google Scholar 

  • Scott DJ, Wilkinson TN, Zhang S, Ferraro T, Wade JD, Tregear GW, et al. Defining the LGR8 residues involved in binding insulin-like peptide 3. Mol Endocrinol. 2007;21(7):1699–712.

    Article  CAS  PubMed  Google Scholar 

  • Scott DJ, Rosengren KJ, Bathgate RA. The different ligand-binding modes of relaxin family peptide receptors RXFP1 and RXFP2. Mol Endocrinol. 2012;26(11):1896–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sedaghat K, Shen PJ, Finkelstein DI, Henderson JM, Gundlach AL. Leucine-rich repeat-containing G-protein-coupled receptor 8 in the rat brain: enrichment in thalamic neurons and their efferent projections. Neuroscience. 2008;156(2):319–33.

    Article  CAS  PubMed  Google Scholar 

  • Seibold JR, Korn JH, Simms R, Clements PJ, Moreland LW, Mayes MD, et al. Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2000;132(11):871–9.

    Article  CAS  PubMed  Google Scholar 

  • Sethi A, Bruell S, Patil N, Hossain MA, Scott DJ, Petrie EJ, et al. The complex binding mode of the peptide hormone H2 relaxin to its receptor RXFP1. Nat Commun. 2016;7:11344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Shabanpoor F, Hughes RA, Zhang S, Bathgate RA, Layfield S, Hossain MA, et al. Effect of helix-promoting strategies on the biological activity of novel analogues of the B-chain of INSL3. Amino Acids. 2010;38(1):121–31.

    Article  CAS  PubMed  Google Scholar 

  • Shabanpoor F, Zhang S, Hughes RA, Hossain MA, Layfield S, Ferraro T, et al. Design and development of analogues of dimers of insulin-like peptide 3 B-chain as high-affinity antagonists of the RXFP2 receptor. Biopolymers. 2011;96(1):81–7.

    Article  CAS  PubMed  Google Scholar 

  • Shemesh R, Toporik A, Levine Z, Hecht I, Rotman G, Wool A, et al. Discovery and validation of novel peptide agonists for G-protein-coupled receptors. J Biol Chem. 2008;283(50):34643–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shemesh R, Hermesh C, Toporik A, Levine Z, Novik A, Wool A, et al. Activation of relaxin-related receptors by short, linear peptides derived from a collagen-containing precursor. Ann N Y Acad Sci. 2009;1160:78–86.

    Article  CAS  PubMed  Google Scholar 

  • Shen PJ, Fu P, Phelan KD, Scott DJ, Layfield S, Tregear GW, et al. Restricted expression of LGR8 in intralaminar thalamic nuclei of rat brain suggests a role in sensorimotor systems. Ann N Y Acad Sci. 2005;1041:510–5.

    Article  CAS  PubMed  Google Scholar 

  • Sherwood OD. Relaxin. In: Knobil E, Neill JD, editors. The physiology of reproduction. 2nd ed. New York: Raven Press; 1994. p. 861–1009.

    Google Scholar 

  • Sherwood OD. Relaxin’s physiological roles and other diverse actions. Endocr Rev. 2004;25(2):205–34.

    Article  CAS  PubMed  Google Scholar 

  • Shpakov AO, Gur’yanov IA, Kuznetsova LA, Plesneva SA, Shpakova EA, Vlasov GP, et al. Studies of the molecular mechanisms of action of relaxin on the adenylyl cyclase signaling system using synthetic peptides derived from the LGR7 relaxin receptor. Neurosci Behav Physiol. 2007;37(7):705–14.

    Article  CAS  PubMed  Google Scholar 

  • Shymko RM, De Meyts P, Thomas R. Logical analysis of timing-dependent receptor signalling specificity: application to the insulin receptor metabolic and mitogenic signalling pathways. Biochem J. 1997;326(Pt 2):463–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silvertown JD, Summerlee AJ, Klonisch T. Relaxin-like peptides in cancer. Int J Cancer. 2003;107(4):513–9.

    Article  CAS  PubMed  Google Scholar 

  • Silvertown JD, Ng J, Sato T, Summerlee AJ, Medin JA. H2 relaxin overexpression increases in vivo prostate xenograft tumor growth and angiogenesis. Int J Cancer. 2006;118(1):62–73.

    Article  CAS  PubMed  Google Scholar 

  • Singh S, Bennett RG. Relaxin signaling activates peroxisome proliferator-activated receptor gamma. Mol Cell Endocrinol. 2010;315(1–2):239–45.

    Article  CAS  PubMed  Google Scholar 

  • Siragy HM, Carey RM. The subtype 2 (AT2) angiotensin receptor mediates renal production of nitric oxide in conscious rats. J Clin Invest. 1997;100(2):264–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith MC, Danielson LA, Conrad KP, Davison JM. Influence of recombinant human relaxin on renal hemodynamics in healthy volunteers. J Am Soc Nephrol. 2006a;17(11):3192–7.

    Article  CAS  PubMed  Google Scholar 

  • Smith MC, Murdoch AP, Danielson LA, Conrad KP, Davison JM. Relaxin has a role in establishing a renal response in pregnancy. Fertil Steril. 2006b;86(1):253–5.

    Article  CAS  PubMed  Google Scholar 

  • Sokol RZ, Wang XS, Lechago J, Johnston PD, Swerdloff RS. Immunohistochemical localization of relaxin in human prostate. J Histochem Cytochem. 1989;37(8):1253–5.

    Article  CAS  PubMed  Google Scholar 

  • Spanel-Borowski K, Schafer I, Zimmermann S, Engel W, Adham IM. Increase in final stages of follicular atresia and premature decay of corpora lutea in Insl3-deficient mice. Mol Reprod Dev. 2001;58(3):281–6.

    Article  CAS  PubMed  Google Scholar 

  • St Louis J, Massicotte G. Chronic decrease of blood pressure by rat relaxin in spontaneously hypertensive rats. Life Sci. 1985;37(14):1351–7.

    Article  CAS  PubMed  Google Scholar 

  • Steinetz BG, Whitaker PG, Edwards JR. Maternal relaxin concentrations in diabetic pregnancy. Lancet. 1992;340(8822):752–5.

    Article  CAS  PubMed  Google Scholar 

  • Sudo S, Kumagai J, Nishi S, Layfield S, Ferraro T, Bathgate RA, et al. 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. 2003;278(10):7855–62.

    Article  CAS  PubMed  Google Scholar 

  • Summerlee AJ, Ramsey DG, Poterski RS. Neutralization of relaxin within the brain affects the timing of birth in rats. Endocrinology. 1998;139(2):479–84.

    Article  CAS  PubMed  Google Scholar 

  • Sunn N, Egli M, Burazin TC, Burns P, Colvill L, Davern P, et al. Circulating relaxin acts on subfornical organ neurons to stimulate water drinking in the rat. Proc Natl Acad Sci U S A. 2002;99(3):1701–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Svendsen AM, Vrecl M, Ellis TM, Heding A, Kristensen JB, Wade JD, et al. Cooperative binding of insulin-like Peptide 3 to a dimeric relaxin family peptide receptor 2. Endocrinology. 2008a;149(3):1113–20.

    Article  CAS  PubMed  Google Scholar 

  • Svendsen AM, Zalesko A, Konig J, Vrecl M, Heding A, Kristensen JB, et al. Negative cooperativity in H2 relaxin binding to a dimeric relaxin family peptide receptor 1. Mol Cell Endocrinol. 2008b;296(1–2):10–7.

    Article  CAS  PubMed  Google Scholar 

  • Szepietowska B, Gorska M, Szelachowska M. Plasma relaxin concentration is related to beta-cell function and insulin sensitivity in women with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2008;79(3):e1–3.

    Article  CAS  PubMed  Google Scholar 

  • Szydlarska D, Grzesiuk W, Trybuch A, Kondracka A, Kowalik I, Bar-Andziak E. Insulin-like factor 3 – a new hormone related to polycystic ovary syndrome? Endokrynol Pol. 2012;63(5):356–61.

    CAS  PubMed  Google Scholar 

  • Tan YY, Wade JD, Tregear GW, Summers RJ. Comparison of relaxin receptors in rat isolated atria and uterus by use of synthetic and native relaxin analogues. Br J Pharmacol. 1998;123(4):762–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan YY, Dawson NF, Kompa AR, Bond CP, Claasz A, Wade JD, et al. Structural requirements for the interaction of sheep insulin-like factor 3 with relaxin receptors in rat atria. Eur J Pharmacol. 2002;457(2–3):153–60.

    Article  CAS  PubMed  Google Scholar 

  • Tao Y-X, Johnson NB, Segaloff DL. Constitutive and agonist-dependent self-association of the cell surface human lutropin receptor. J Biol Chem. 2004;279(7):5904–14.

    Article  CAS  PubMed  Google Scholar 

  • Tashima LS, Mazoujian G, Bryant-Greenwood GD. Human relaxins in normal, benign and neoplastic breast tissue. J Mol Endocrinol. 1994;12(3):351–64.

    Article  CAS  PubMed  Google Scholar 

  • Teerlink JR, Metra M, Felker GM, Ponikowski P, Voors AA, Weatherley BD, et al. Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet. 2009;373(9673):1429–39.

    Article  CAS  PubMed  Google Scholar 

  • Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet. 2013;381(9860):29–39.

    Article  CAS  PubMed  Google Scholar 

  • Teichman SL, Unemori E, Dschietzig T, Conrad K, Voors AA, Teerlink JR, et al. Relaxin, a pleiotropic vasodilator for the treatment of heart failure. Heart Fail Rev. 2009;14(4):321–9.

    Article  CAS  PubMed  Google Scholar 

  • Telgmann R, Gellersen B. Marker genes of decidualization: activation of the decidual prolactin gene. Hum Reprod Update. 1998;4(5):472–9.

    Article  CAS  PubMed  Google Scholar 

  • Thanasupawat T, Glogowska A, Burg M, Wong GW, Hoang-Vu C, Hombach-Klonisch S, et al. RXFP1 is targeted by complement C1q tumor necrosis factor-related factor 8 in brain cancer. Front Endocrinol. 2015;6:127.

    Article  Google Scholar 

  • Thomas GR, Vandlen R. The purely chronotropic effects of relaxin in the rat isolated heart. J Pharm Pharmacol. 1993;45(10):927–8.

    Article  CAS  PubMed  Google Scholar 

  • Thompson VC, Morris TG, Cochrane DR, Cavanagh J, Wafa LA, Hamilton T, et al. Relaxin becomes upregulated during prostate cancer progression to androgen independence and is negatively regulated by androgens. Prostate. 2006;66(16):1698–709.

    Article  CAS  PubMed  Google Scholar 

  • Toth M, Taskinen P, Ruskoaho H. Relaxin stimulates atrial natriuretic peptide secretion in perfused rat heart. J Endocrinol. 1996;150(3):487–95.

    Article  CAS  PubMed  Google Scholar 

  • Unemori EN, Pickford LB, Salles AL, Piercy CE, Grove BH, Erikson ME, et al. Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo. J Clin Invest. 1996;98(12):2739–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Unemori EN, Erikson ME, Rocco SE, Sutherland KM, Parsell DA, Mak J, et al. Relaxin stimulates expression of vascular endothelial growth factor in normal human endometrial cells in vitro and is associated with menometrorrhagia in women. Hum Reprod. 1999;14(3):800–6.

    Article  CAS  PubMed  Google Scholar 

  • Unemori EN, Lewis M, Constant J, Arnold G, Grove BH, Normand J, et al. Relaxin induces vascular endothelial growth factor expression and angiogenesis selectively at wound sites. Wound Repair Regen. 2000;8(5):361–70.

    Article  CAS  PubMed  Google Scholar 

  • van der Westhuizen ET, Halls ML, Samuel CS, Bathgate RA, Unemori EN, Sutton SW, et al. Relaxin family peptide receptors – from orphans to therapeutic targets. Drug Discov Today. 2008;13(15–16):640–51.

    Article  PubMed  CAS  Google Scholar 

  • Vasilenko P, Mead JP, Weidmann JE. Uterine growth-promoting effects of relaxin: a morphometric and histological analysis. Biol Reprod. 1986;35(4):987–95.

    Article  CAS  PubMed  Google Scholar 

  • Velez-Ruiz GA, Sunahara RK. Reconstitution of g protein-coupled receptors into a model bilayer system: reconstituted high-density lipoprotein particles. Methods Mol Biol. 2011;756:167–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wade JD, Layden SS, Lambert PF, Kakouris H, Tregear GW. Primate relaxin: synthesis of gorilla and rhesus monkey relaxins. J Protein Chem. 1994;13:315–21.

    Article  CAS  PubMed  Google Scholar 

  • Wang P, Li HW, Wang YP, Chen H, Zhang P. Effects of recombinant human relaxin upon proliferation of cardiac fibroblast and synthesis of collagen under high glucose condition. J Endocrinol Investig. 2009;32(3):242–7.

    Article  CAS  Google Scholar 

  • Ward DG, Thomas GR, Cronin MJ. Relaxin increases rat heart rate by a direct action on the cardiac atrium. Biochem Biophys Res Commun. 1992;186(2):999–1005.

    Article  CAS  PubMed  Google Scholar 

  • Weiss G. Relaxin in the male. Biol Reprod. 1989;40(2):197–200.

    Article  CAS  PubMed  Google Scholar 

  • Whittaker PG, Edwards JR, Randolph C, Bullesbach EE, Schwabe C, Steinetz BG. Abnormal relaxin secretion during pregnancy in women with type 1 diabetes. Exp Biol Med. 2003;228(1):33–40.

    CAS  Google Scholar 

  • Whorton MR, Bokoch MP, Rasmussen SG, Huang B, Zare RN, Kobilka B, et al. A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein. Proc Natl Acad Sci U S A. 2007;104(18):7682–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wiedemar N, Tetens J, Jagannathan V, Menoud A, Neuenschwander S, Bruggmann R, et al. Independent polled mutations leading to complex gene expression differences in cattle. PLoS One. 2014;9(3):e93435.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Willoughby D, Baillie GS, Lynch MJ, Ciruela A, Houslay MD, Cooper DM. Dynamic regulation, desensitization, and cross-talk in discrete subcellular microdomains during beta2-adrenoceptor and prostanoid receptor cAMP signaling. J Biol Chem. 2007;282(47):34235–49.

    Article  CAS  PubMed  Google Scholar 

  • Winslow JW, Shih A, Bourell JH, Weiss G, Reed B, Stults JT, et al. Human seminal relaxin is a product of the same gene as human luteal relaxin. Endocrinology. 1992;130(5):2660–8.

    Article  CAS  PubMed  Google Scholar 

  • Xiao J, Chen CZ, Huang Z, Agoulnik IU, Ferrer M, Southall N, et al. Discovery, optimization and biological activity of the first potent and selective small-molecule agonist series of the human relaxin hormone receptor RXFP1. report NP; 2012.

    Google Scholar 

  • Xiao J, Huang Z, Chen CZ, Agoulnik IU, Southall N, Hu X, et al. Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1. Nat Commun. 2013;4:1–7.

    Google Scholar 

  • Xu Q, Lekgabe ED, Gao XM, Ming Z, Tregear GW, Dart AM, et al. Endogenous relaxin does not affect chronic pressure overload-induced cardiac hypertrophy and fibrosis. Endocrinology. 2008;149(2):476–82.

    Article  CAS  PubMed  Google Scholar 

  • Xu Q, Chakravorty A, Bathgate RA, Dart AM, Du XJ. Relaxin therapy reverses large artery remodeling and improves arterial compliance in senescent spontaneously hypertensive rats. Hypertension. 2010;55(5):1260–6.

    Article  CAS  PubMed  Google Scholar 

  • Yan Y, Scott DJ, Wilkinson TN, Ji J, Tregear GW, Bathgate RA. Identification of the N-linked glycosylation sites of the human relaxin receptor and effect of glycosylation on receptor function. Biochemistry. 2008;47(26):6953–68.

    Article  CAS  PubMed  Google Scholar 

  • Yki JH, Wahlstrom T, Seppala M. Immunohistochemical demonstration of relaxin in the genital tract of men. J Reprod Fertil. 1983;69(2):693–5.

    Article  Google Scholar 

  • Yoshida T, Kumagai H, Kohsaka T, Ikegaya N. Relaxin protects against renal ischemia-reperfusion injury. Am J Physiol Ren Physiol. 2013;305(8):F1169–76.

    Article  CAS  Google Scholar 

  • Zhang Q, Liu SH, Erikson M, Lewis M, Unemori E. Relaxin activates the MAP kinase pathway in human endometrial stromal cells. J Cell Biochem. 2002;85(3):536–44.

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Qi YF, Geng B, Pan CS, Zhao J, Chen L, et al. Effect of relaxin on myocardial ischemia injury induced by isoproterenol. Peptides. 2005;26(9):1632–9.

    Article  CAS  PubMed  Google Scholar 

  • Zhang S, Hughes RA, Bathgate RA, Shabanpoor F, Hossain MA, Lin F, et al. Role of the intra-A-chain disulfide bond of insulin-like peptide 3 in binding and activation of its receptor, RXFP2. Peptides. 2010;31(9):1730–6.

    Article  CAS  PubMed  Google Scholar 

  • Zhao L, Roche PJ, Gunnersen JM, Hammond VE, Tregear GW, Wintour EM, et al. Mice without a functional relaxin gene are unable to deliver milk to their pups. Endocrinology. 1999;140(1):445–53.

    Article  CAS  Google Scholar 

  • Zimmermann S, Schottler P, Engel W, Adham IM. Mouse Leydig insulin-like (Ley I-L) gene: structure and expression during testis and ovary development. Mol Reprod Dev. 1997;47(1):30–8.

    Article  CAS  PubMed  Google Scholar 

  • Zimmermann S, Steding G, Emmen JM, Brinkmann AO, Nayernia K, Holstein AF, et al. Targeted disruption of the INSL3 gene causes bilateral cryptorchidism. Mol Endocrinol. 1999;13(5):681–91.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC, 3052, Australia

    Roger J. Summers & Michelle L. Halls

  2. Neuropeptides Division, Florey Institute of Neuroscience and Mental Health and Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, 3010, Australia

    Ross A. D. Bathgate

Authors
  1. Roger J. Summers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michelle L. Halls
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ross A. D. Bathgate
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roger J. Summers .

Editor information

Editors and Affiliations

  1. Dept. Biological Science, Department of Molecular Science and Tech College of Natural Science, Suwon, Korea (Republic of)

    Sangdun Choi

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media LLC

About this entry

Cite this entry

Summers, R.J., Halls, M.L., Bathgate, R.A.D. (2016). Relaxin Family Peptide Receptors RXFP1 and RXFP2. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6438-9_362-1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-6438-9_362-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-6438-9

  • Online ISBN: 978-1-4614-6438-9

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation