A Novel Antagonist Peptide Reveals a Physiological Role of Insulin-Like Peptide 5 in Control of Colorectal Function.

Insulin-like peptide 5 (INSL5), the natural ligand for the relaxin family peptide receptor 4 (RXFP4), is a gut hormone that is exclusively produced by colonic L-cells. We have recently developed an analogue of INSL5, INSL5-A13, that acts as an RXFP4 agonist in vitro and stimulates colorectal propulsion in wild-type mice but not in RXFP4-knockout mice. These results suggest that INSL5 may have a physiological role in the control of colorectal motility. To investigate this possibility, in this study we designed and developed a novel INSL5 analogue, INSL5-A13NR. This compound is a potent antagonist, without significant agonist activity, in two in vitro assays. We report here for the first time that this novel antagonist peptide blocks agonist-induced increase in colon motility in mice that express RXFP4. Our data also show that colorectal propulsion induced by intracolonic administration of bacterial products (short-chain fatty acids, SCFAs) is antagonized by INSL5-A13NR. Therefore, INSL5-A13NR is an important research tool and potential drug lead for the treatment of colon motility disorders, such as bacterial diarrheas.

Understanding relaxin signalling at the cellular level.

The peptide hormone relaxin mediates many biological actions including anti-fibrotic, vasodilatory, angiogenic, anti-inflammatory, anti-apoptotic, and organ protective effects across a range of tissues. At the cellular level, relaxin binds to the G protein-coupled receptor relaxin family peptide receptor 1 (RXFP1) to activate a variety of downstream signal transduction pathways. This signalling cascade is complex and also varies in diverse cellular backgrounds. Moreover, RXFP1 signalling shows crosstalk with other receptors to mediate some of its physiological functions. This review summarises known signalling pathways induced by acute versus chronic treatment with relaxin across a range of cell types, it describes RXFP1 crosstalk with other receptors, signalling pathways activated by other ligands targeting RXFP1, and it also outlines physiological relevance of RXFP1 signalling outputs. Comprehensive understanding of the mechanism of relaxin actions in fibrosis, vasodilation, as well as organ protection, will further support relaxin's clinical potential.