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Gene Review

RLN3  -  relaxin 3

Homo sapiens

Synonyms: H3, INSL7, Insulin-like peptide 7, Insulin-like peptide INSL7, Prorelaxin H3, ...
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Disease relevance of RLN3


Psychiatry related information on RLN3


High impact information on RLN3

  • Here, we report the solution structure of human relaxin-3, the first structure of a relaxin family member to be solved by NMR methods [5].
  • Overall, relaxin-3 adopts an insulin-like fold, but the structure differs crucially from the crystal structure of human relaxin-2 near the B-chain terminus [5].
  • Here, we demonstrate that H3 relaxin activates LGR7 but not LGR8 [6].
  • Surprisingly, GPCR142 was activated by nanomolar concentrations of relaxin-3 but was completely unresponsive to all other known insulin-like peptides [7].
  • In the accompanying article (Liu, C., Eriste, E., Sutton, S., Chen, J., Roland, B., Kuei, C., Farmer, N., Jörnvall, H., Sillard, R., and Lovenberg, T. W. (2003) J. Biol. Chem. 278, 50754-50764), we present the case that relaxin-3, which has previously been shown to bind to the relaxin receptor LGR7, is most likely the endogenous ligand for GPCR135 [7].

Biological context of RLN3

  • The presence of relaxin-3 and these receptors in the PVN led us to investigate the effect of central administration of relaxin-3 on food intake in male Wistar rats [1].
  • Recombinant mouse prorelaxin-3 demonstrated similar activity to H3 relaxin, suggesting that the presence of the C peptide did not influence the conformation of the active site [8].
  • These results suggest a novel role for relaxin-3 in appetite regulation [1].
  • We have identified a novel human relaxin gene, designated H3 relaxin, and an equivalent relaxin gene in the mouse from the Celera Genomics data base [9].
  • Consistent with the distribution of RLX3 mRNA, neurons containing RLX3-like immunoreactivity (LI) were observed in the pontine nucleus incertus and the majority of these cells, which are known to express corticotropin-releasing factor receptor-1, were shown to express glutamic acid decarboxylase-65-immunoreactivity, suggesting a GABA phenotype [10].

Anatomical context of RLN3

  • Relaxin-3 mRNA is expressed in the nucleus incertus of the brainstem, which has projections to the hypothalamus [1].
  • In situ hybridization showed that relaxin-3 mRNA is predominantly expressed in the dorsomedial ventral tegmental nucleus of the brainstem (aka nucleus incertus), as well as in discrete cells in the lateral periaqueductal gray and in the central gray nucleus [11].
  • A peptide derived from the likely proteolytic processing of the H3 relaxin prohormone sequence was synthesized and found to possess relaxin activity in bioassays utilizing the human monocytic cell line, THP-1, that expresses the relaxin receptor [9].
  • Relaxin-3 in GABA projection neurons of nucleus incertus suggests widespread influence on forebrain circuits via G-protein-coupled receptor-135 in the rat [10].
  • Plasma thyroid stimulating hormone was significantly decreased after acute and repeated administration of H3 [12].

Associations of RLN3 with chemical compounds

  • However, relaxin-3 does not stimulate a Ca(2+) response in cells coexpressing Galpha(16) and mouse GPCR142, whereas it does for cells expressing GPCR142 from other species tested [13].
  • In this report, we demonstrate that bradykinin activates neither GPCR135 nor GPCR142, whereas relaxin-3 does [13].
  • These data indicate FR190997 and relaxin 3 as selective agonists for hB(2)R and hGPR100, respectively, and support the concept that different agonists may specifically bias the conformational states of a receptor to result in a final common G protein coupling, which is differentially recognized by antagonists [14].
  • FR190997 and relaxin 3 responses at the hB(2)R and hGPR100, respectively, were not inhibited by Icatibant (1 microM) [14].
  • Solid phase synthesis of the separate, selectively S-protected A and B chains followed by their purification and the subsequent stepwise formation of each of the three disulfides led to the successful acquisition of human relaxin-3 [15].

Physical interactions of RLN3


Regulatory relationships of RLN3

  • H3 relaxin was also able to activate native LGR7 receptors [8].
  • Relaxin-3 was found to bind to and activate native relaxin receptors in vitro and stimulate water drinking through central relaxin receptors in vivo [15].

Other interactions of RLN3

  • We have created chimeric peptides that consist of the B-chain of human relaxin-3 in combination with various A-chains from other members of the relaxin/insulin family [16].
  • The relaxin-3/INSL5 chimeric peptide is a potential tool to study in vivo function of GPCR135 [16].
  • H3 relaxin is a specific ligand for LGR7 and activates the receptor by interacting with both the ectodomain and the exoloop 2 [6].
  • Thus, we tested whether GPCR142 could also respond to relaxin-3 or related insulin-like molecules [7].
  • These results suggested that activation of LGR7 by H3 relaxin involves specific binding of the ligand to both the ectodomain and the exoloop 2, thus providing a model with which to understand the molecular basis of ligand signaling for this unique subgroup of G protein-coupled receptors [6].

Analytical, diagnostic and therapeutic context of RLN3

  • In ongoing studies to understand the physiological functions of RLX3, the distribution of RLX3-containing neuronal elements in rat brain was determined by immunohistochemistry, using an affinity-purified polyclonal antiserum raised against a conserved segment of the RLX3 C-peptide (AS-R3(85-101)) [10].
  • Thus, a large number of wasp-allergic patients with RXN3 responses could not be offered immunotherapy [17].


  1. Central relaxin-3 administration causes hyperphagia in male Wistar rats. McGowan, B.M., Stanley, S.A., Smith, K.L., White, N.E., Connolly, M.M., Thompson, E.L., Gardiner, J.V., Murphy, K.G., Ghatei, M.A., Bloom, S.R. Endocrinology (2005) [Pubmed]
  2. Theatre footwear: a health hazard? Thomas, J.A., Fligelstone, L.J., Jerwood, T.E., Rees, R.W. The British journal of theatre nursing : NATNews : the official journal of the National Association of Theatre Nurses. (1993) [Pubmed]
  3. Identification of an histone H3 acetylated/K4-methylated-bound intragenic enhancer regulatory for urokinase receptor expression. Wang, H., Yan, C., Asangani, I., Allgayer, H., Boyd, D.D. Oncogene (2007) [Pubmed]
  4. Chronic intracerebroventricular administration of relaxin-3 increases body weight in rats. Hida, T., Takahashi, E., Shikata, K., Hirohashi, T., Sawai, T., Seiki, T., Tanaka, H., Kawai, T., Ito, O., Arai, T., Yokoi, A., Hirakawa, T., Ogura, H., Nagasu, T., Miyamoto, N., Kuromitsu, J. J. Recept. Signal Transduct. Res. (2006) [Pubmed]
  5. Solution structure and novel insights into the determinants of the receptor specificity of human relaxin-3. Rosengren, K.J., Lin, F., Bathgate, R.A., Tregear, G.W., Daly, N.L., Wade, J.D., Craik, D.J. J. Biol. Chem. (2006) [Pubmed]
  6. H3 relaxin is a specific ligand for LGR7 and activates the receptor by interacting with both the ectodomain and the exoloop 2. Sudo, S., Kumagai, J., Nishi, S., Layfield, S., Ferraro, T., Bathgate, R.A., Hsueh, A.J. J. Biol. Chem. (2003) [Pubmed]
  7. Identification of relaxin-3/INSL7 as a ligand for GPCR142. Liu, C., Chen, J., Sutton, S., Roland, B., Kuei, C., Farmer, N., Sillard, R., Lovenberg, T.W. J. Biol. Chem. (2003) [Pubmed]
  8. Relaxin-3: improved synthesis strategy and demonstration of its high-affinity interaction with the relaxin receptor LGR7 both in vitro and in vivo. Bathgate, R.A., Lin, F., Hanson, N.F., Otvos, L., Guidolin, A., Giannakis, C., Bastiras, S., Layfield, S.L., Ferraro, T., Ma, S., Zhao, C., Gundlach, A.L., Samuel, C.S., Tregear, G.W., Wade, J.D. Biochemistry (2006) [Pubmed]
  9. Human relaxin gene 3 (H3) and the equivalent mouse relaxin (M3) gene. Novel members of the relaxin peptide family. Bathgate, R.A., Samuel, C.S., Burazin, T.C., Layfield, S., Claasz, A.A., Reytomas, I.G., Dawson, N.F., Zhao, C., Bond, C., Summers, R.J., Parry, L.J., Wade, J.D., Tregear, G.W. J. Biol. Chem. (2002) [Pubmed]
  10. Relaxin-3 in GABA projection neurons of nucleus incertus suggests widespread influence on forebrain circuits via G-protein-coupled receptor-135 in the rat. Ma, S., Bonaventure, P., Ferraro, T., Shen, P.J., Burazin, T.C., Bathgate, R.A., Liu, C., Tregear, G.W., Sutton, S.W., Gundlach, A.L. Neuroscience (2007) [Pubmed]
  11. Identification of relaxin-3/INSL7 as an endogenous ligand for the orphan G-protein-coupled receptor GPCR135. Liu, C., Eriste, E., Sutton, S., Chen, J., Roland, B., Kuei, C., Farmer, N., Jörnvall, H., Sillard, R., Lovenberg, T.W. J. Biol. Chem. (2003) [Pubmed]
  12. Effects of acute and chronic relaxin-3 on food intake and energy expenditure in rats. McGowan, B.M., Stanley, S.A., Smith, K.L., Minnion, J.S., Donovan, J., Thompson, E.L., Patterson, M., Connolly, M.M., Abbott, C.R., Small, C.J., Gardiner, J.V., Ghatei, M.A., Bloom, S.R. Regul. Pept. (2006) [Pubmed]
  13. Pharmacological characterization of relaxin-3/INSL7 receptors GPCR135 and GPCR142 from different mammalian species. Chen, J., Kuei, C., Sutton, S.W., Bonaventure, P., Nepomuceno, D., Eriste, E., Sillard, R., Lovenberg, T.W., Liu, C. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  14. Bradykinin B2 and GPR100 receptors: a paradigm for receptor signal transduction pharmacology. Meini, S., Bellucci, F., Cucchi, P., Giuliani, S., Quartara, L., Giolitti, A., Zappitelli, S., Rotondaro, L., Boels, K., Maggi, C.A. Br. J. Pharmacol. (2004) [Pubmed]
  15. The chemistry and biology of human relaxin-3. Tregear, G.W., Bathgate, R.A., Layfield, S., Ferraro, T., Gundlach, A., Ma, S., Lin, F., Hanson, N.F., Summers, R.J., Rosengren, J., Craik, D.J., Wade, J.D. Ann. N. Y. Acad. Sci. (2005) [Pubmed]
  16. Relaxin-3/insulin-like peptide 5 chimeric peptide, a selective ligand for G protein-coupled receptor (GPCR)135 and GPCR142 over leucine-rich repeat-containing G protein-coupled receptor 7. Liu, C., Chen, J., Kuei, C., Sutton, S., Nepomuceno, D., Bonaventure, P., Lovenberg, T.W. Mol. Pharmacol. (2005) [Pubmed]
  17. Allergy to stinging and biting insects in Queensland. Solley, G.O. Med. J. Aust. (1990) [Pubmed]
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