Editors' ChoiceReproductive Biology

The Long and the Short of Relaxin Signaling

Science's STKE  21 Nov 2006:
Vol. 2006, Issue 362, pp. tw396
DOI: 10.1126/stke.3622006tw396

The hormone relaxin functions in the reproductive system and derived its name from its role in relaxation of the pubic symphysis during parturition. Relaxin and the related hormone insulin-like peptide 3 (INSL3) act through heterotrimeric guanine nucleotide­-binding protein (G protein)-coupled receptors (GPCRs). Scott et al. report studies of human splice variants of these proteins that reveal an unusual mode of signaling by these receptors. The receptors for relaxin and INSL3, called LGR7 (leucine-rich repeat-containing GPCR 7) and LGR8, respectively [or, in an alternative nomenclature, relaxin family peptide receptors 1 and 2 (RXFP1 and RXFP2)] differ from other GPCRs in that they contain N-terminal domains with similarity to the ligand-binding domains of low-density lipoprotein class A (LDLa). Splice variants exist in which this LDLa module is missing or in which a secreted protein mainly encoding just the LDLa module is made. The authors examined the signaling properties of natural or artificial variant receptors in transfected cells. Although they bound relaxin normally, LGR7 variants without the LDLa module failed to produce their normal G protein-coupled signaling effects on accumulation of cyclic AMP. The truncated excreted form inhibited signaling from the normal receptor. It is not yet clear precisely how the LDLa modules influence signaling. In LDL receptors, these modules are binding sites for ligands or for protein-protein interactions. The truncated, excreted form of LDL7 was detected in human uterus and brain and was most abundant in uteri of pregnant mice. Thus, the authors propose that LGR7 and LGR8 have an unusual mechanism of GPCR signaling and that the alternative splicing of the receptors may produce an inhibitory factor that provides an additional regulatory mechanism for controlling relaxin action during reproduction.

D. J. Scott, S. Layfield, Y. Yan, S. Sudo, A. J. W. Hsueh, G. W. Tregear, R. A. D. Bathgate, Characterization of novel splice variants of LGR7 and LGR8 reveals that receptor signaling is mediated by their unique low density lipoprotein class A modules. J. Biol. Chem. 281, 34942-34954 (2006). [Abstract] [Full Text]