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The LGR7/RXFP1 and LGR8/RXFP2 receptors are unique receptors among the G-protein-coupled receptors (GPCRs) in having a low-density lipoprotein class A (LDL-A) module. Their complex gene organization, among the intron-richest of the GPCRs, suggests that alternative splicing is a common occurrence. We have therefore investigated the role of the LDL-A module and shown the identity, expression, and functions of three LGR7 splice variants in the human decidua. Point mutations of conserved residues or complete deletion of the LDL-A module resulted in loss of the cAMP response to relaxin. Its glycosylation also impacted LGR7 cell surface delivery and therefore receptor activation. The wild-type (WT) LGR7 was expressed as both precursor and mature forms, but deletion of the LDL-A module resulted in expression of only the mature form. Three new alternatively spliced variants of LGR7 were identified, all containing a truncated extracellular region. Their functional characterization showed them exerting dominant negative effects on the WT LGR7 by preventing its homodimerization, maturation, and subsequent trafficking to the cell surface, resulting in loss of function. In summary, different mechanisms have been identified for controlling the cell surface expression and function of the LGR7 protein which are likely to be significant for the role of relaxin in human parturition.

The decidua of the human maternal-fetal interface is a local source of intrauterine relaxin, and the choriodecidua expresses its receptor (LGR7). Since these tissues consist of a variety of cells, we sought to identify the primary cell(s) responsible for LGR7 expression and relaxin responsiveness.

Relaxin in human pregnancy is both a systemic hormone from the corpus luteum and an autocrine/paracrine hormone at the maternal-fetal interface formed by the decidua/placenta and fetal membranes. We have focused our studies on the autocrine/paracrine roles of relaxin, especially in the preterm premature rupture of the fetal membranes, which causes 30-40% of preterm births. By using different techniques and different tissue collections, our laboratory has shown that expression of the relaxin genes and proteins in the decidua and placenta is increased in patients with preterm premature rupture of the fetal membranes. Relaxin binding and the expression of LGR7 are primarily in the chorion and decidua and are downregulated after spontaneous labor and delivery both at term and preterm. However, expression of LGR7 in the fetal membranes is significantly greater in all clinical situations at preterm than term, suggesting an important role for relaxin in these tissues at that time. The roles of the relaxin system in three potential causes of preterm birth are discussed: in the growth and proliferation of the membranes important for fetal membrane accommodation to fetal and placental growth, in acute infection, and in the inflammatory response leading to the initiation of labor.