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| ENDOCRINOLOGY: Time to relax
The hormone relaxin has been matched up with the orphan leucine-rich G-protein-coupled receptors LGR7 and LGR8. The hormone relaxin favours the growth and remodelling of reproductive tissues during pregnancy. But despite the fact that relaxin was one of the first reproductive hormones to be identified, its receptor has remained undiscovered. Hsu and colleagues now report in Science that they have matched up the lonely hormone with the orphan receptors LGR7 and LGR8.
Although relaxin is structurally related to insulin, some data indicated that it might bind to a G-protein-coupled receptor (GPCR) instead of a tyrosine-kinase receptor. So, the authors tested whether any of the orphan leucine-rich GPCRs (LGRs) might be the missing relaxin receptor. They expressed LGR7 or its relative LGR8 (which was discovered based on GenBank searches for genes with similar structure to glycoprotein hormone receptors) in cells and found that relaxin could indeed increase cyclic AMP levels in these cells in a dose-dependent manner, whereas it had no effect on cells that did not express these receptors. Crosslinking analysis showed that relaxin can bind to the extracellular domain of LGR7. Moreover, the soluble extracellular domain of LGR7 inhibited the effect of relaxin on cells. This inhibition was also observed in vivo, as pregnant mice treated with the extracellular domain of LGR7 had a delayed birth and reduced nipple size. But the two receptors are expressed in many tissues, indicating that relaxin is far more versatile than just a pregnancy hormone. This is consistent with studies in humans, which have shown that, among other functions, relaxin is also important for cardiac function and for the formation of new blood vessels. In rats, mice and other model organisms, relaxin functions during late pregnancy, when it promotes growth and dilation of the cervix, growth and quiescence of the uterus, and growth and development of the mammary gland and nipple. So, the authors suggest that the development of agonists and antagonists for its newly discovered receptors might help to solve problems related to preterm labour and delivery. In humans, however, as Richard Ivell points out in an accompanying Perspectives article, relaxin peaks during the first term of pregnancy, and is probably involved in implantation of the fetus. Whatever the exact function of relaxin, it is safe to say that the discovery of its receptors is bound to accelerate research on this versatile hormone. Raluca Gagescu References | | ||||||||||
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