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Relaxin-3:  Improved Synthesis Strategy and Demonstration of Its High-Affinity Interaction with the Relaxin Receptor LGR7 Both In Vitro and In Vivo

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Howard Florey Institute, University of Melbourne, Melbourne, Victoria 3010, Australia, The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, and BresaGen Ltd., Post Office Box 259 Rundle Mall, Adelaide, South Australia 5000, Australia
Cite this: Biochemistry 2006, 45, 3, 1043–1053
Publication Date (Web):December 22, 2005
Copyright © 2006 American Chemical Society

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    Relaxin-3 is a member of the human relaxin peptide family, the gene for which, RLN3, is predominantly expressed in the brain. Mapping studies in the rodent indicate a highly developed network of RLN3, RLN1, and relaxin receptor-expressing cells in the brain, suggesting that relaxin peptides have important functional roles in the central nervous system. A regioselective disulfide-bond synthesis protocol was developed and used for the chemical synthesis of human (H3) relaxin-3. The selectively S-protected A and B chains were combined by stepwise formation of each of the three insulin-like disulfides via aeration, thioloysis, and iodolysis. Judicious positioning of the three sets of S-protecting groups was crucial for acquisition of synthetic H3 relaxin in a good overall yield. The activity of the peptide was tested against relaxin family peptide receptors. Although the highest activity was demonstrated on the human relaxin-3 receptor (GPCR135), the peptide also showed high activity on relaxin receptors (LGR7) from various species and variable activity on the INSL3 receptor (LGR8). 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. H3 relaxin was also able to activate native LGR7 receptors. It stimulated increased MMP-2 expression in LGR7-expressing rat ventricular fibroblasts in a dose-dependent manner and, following infusion into the lateral ventricle of the brain, stimulated water drinking in rats, activating LGR7 receptors located in the subfornical organ. Thus, H3 relaxin is able to interact with the relaxin receptor LGR7 both in vitro and in vivo.

     This work was supported by an Institute Block Grant (reg. key 983001) from the NHMRC to the Howard Florey Institute and by NHMRC Project Grants (350284 and 30012) to J.D.W., R.A.D.B., and G.W.T.

     Howard Florey Institute, University of Melbourne.


     The Wistar Institute.

     BresaGen Ltd.


     To whom correspondence should be addressed:  Howard Florey Institute, University of Melbourne, Melbourne, Victoria 3010, Australia. Telephone:  +61-3-8344-7285. Fax:  +61-3-9348-1707. E-mail: [email protected].

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