Evolution of the signaling system in relaxin-family peptides

Recent studies have characterized two G-protein-coupled receptors (GPCRs), LGR7 and LGR8, as relaxin receptors. Later studies have shown that LGR7 and LGR8 also are cognate receptors for the relaxin-family peptides, INSL7/relaxin3 and INSL3, respectively. In addition, INSL7/relaxin3 signals through two orphan GPCRs, GPCR135 and GPCR142, whereas INSL5 is a select ligand for GPCR142. These findings have greatly enhanced our understanding of the physiology and signaling of this unique group of peptide hormones. Phylogenetic analysis of relaxin-family peptides and their co-evolved receptors suggests that the ancestor relaxin gene duplicated multiple times in a vertebrate branch-specific manner. Among the seven human relaxin-family peptides (relaxin1, relaxin2, INSL3/RLF, INSL4/EPIL, INSL5/RIF2, INSL6/RIF1, and INSL7/relaxin3), INSL7 and INSL5 could represent the most ancient form. By contrast, the most widely studied family peptides, human relaxins H1 and H2, appear to be derived from recent gene duplication in mammals. Therefore, relaxin-family peptides could be important for the evolution and adaptation to lineage-specific physiologic processes during evolution. Duplicated relaxin-family genes assumed regulatory roles in newly evolved reproductive processes, and relaxin/LGR signaling was harnessed for signaling in the uterus and mammary gland in addition to other tissues. Although the precise evolutionary history of relaxin ligand/receptor pairs remains to be elucidated, these findings indicate that the expansion of relaxin-family genes and their specific regulatory functions have evolved during vertebrate evolution to allow the development of a tissue-specific regulatory mechanism in a lineage-specific manner and provide a revealing portrait of molecular evolution in action.