Relaxin is a heterodimeric peptide hormone produced by the corpus luteum, decidua, and placenta in pregnant and nonpregnant females attaining the highest plasma levels during pregnancy. Other than its role in the inhibition of uterine contractile activity, relaxin has been shown to effect the induction of collagen remodeling and the consequent softening of the tissues of the birth canal (cervix and vagina), growth and differentiation of the mammary gland, and dilation of the blood vessels. Thus, relaxin plays a significant role in the overall regulation of physiological adaptation during pregnancy. Based on: primary and secondary structural characteristics, relaxin was grouped with insulin and insulin-like growth factors (IGFs) as a structural homolog. Analogous to insulin, prorelaxin, the precursor form of relaxin, has a domain arrangement similar to insulin and IGF precursors; mature relaxin appears to be processed by convertases to generate a two-chain heterodimer from the prorelaxin. In addition to two almost identical relaxin genes in human, there are five additional relaxin family genes including those encoding INSL3/RLF, INSIA/EPIL, INSL5/RIF2, INSL6/RIF1, and relaxin3. Passive immunization with anti-relaxin antibodies during the anteparmm period reduces cervical growth and extensibility as well as disrupts birth in rodents. In addition, numerous studies have shown that serum relaxin is an independent predictor of the risk of preterm delivery at multiple stages of pregnancy in humans. These earlier studies have propelled the proposition that a reduction of relaxin activity through receptor antagonists or immunization could be important for the treatment of preterm labor and birth in conjunction with traditional methods targeting other signaling pathways. Our recent studies have established that relaxin activates two orphan G protein-coupled receptors, LGR7 and LGR8 (Hsu et al., 2002. Science 295:671-4) as well as the cAMP-dependent pathway in target cells, whereas the closely related relaxin3 and INSL3 are selective agonists for LGR7 and LGR8, respectively. To take advantage of these new findings in relaxin signaling for the benefit of reproductive health research, we propose to screen for mutant recombinant relaxin antagonists that retain receptor-binding activity while being devoid of receptor-activation activity. Once mutant peptides with only the receptor binding activity are obtained, the antagonistic effect of these peptides will be tested in co-treatment assays to determine whether the mutant peptides are capable of antagonizing the relaxin-induced cAMP production in LGR7- and LGR8- expressing cells as well as delaying parturition in pregnant rats in vivo. These antagonists could be used to block relaxin action during preterm labor as well as provide a tool for further research on the role of LGR7 and LGR8 in reproductive tract physiology. ? ?

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Human Embryology and Development Subcommittee 1 (HED)
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Ilekis, John V
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Stanford University
Obstetrics & Gynecology
Schools of Medicine
United States
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Park, Jae-Il; Semyonov, Jenia; Yi, Wei et al. (2008) Regulation of receptor signaling by relaxin A chain motifs: derivation of pan-specific and LGR7-specific human relaxin analogs. J Biol Chem 283:32099-109
Semyonov, Jenia; Park, Jae-Il; Chang, Chia Lin et al. (2008) GPCR genes are preferentially retained after whole genome duplication. PLoS One 3:e1903
Park, Jae-Il; Semyonov, Jenia; Chang, Chia Lin et al. (2008) Origin of INSL3-mediated testicular descent in therian mammals. Genome Res 18:974-85
Dissen, Gregory A; Garcia-Rudaz, Cecilia; Tapia, Veronica et al. (2006) Expression of the insulin receptor-related receptor is induced by the preovulatory surge of luteinizing hormone in thecal-interstitial cells of the rat ovary. Endocrinology 147:155-65