The relaxin family peptide receptor 1 (RXFP1): An emerging player in human health and disease

Abstract

Background: Relaxin/relaxin family peptide receptor 1 (RXFP1) signaling is important for both normal physiology and disease. Strong preclinical evidence supports relaxin as a potent antifibrotic molecule. However, relaxin-based therapy failed in clinical trial in patients with systemic sclerosis. We and others have discovered that aberrant expression of RXFP1 may contribute to the abnormal relaxin/RXFP1 signaling in different diseases. Reduced RXFP1 expression and alternative splicing transcripts with potential functional consequences have been observed in fibrotic tissues. A relative decrease in RXFP1 expression in fibrotic tissues-specifically lung and skin-may explain a potential insensitivity to relaxin. In addition, receptor dimerization also plays important roles in relaxin/RXFP1 signaling.

Methods: This review describes the tissue specific expression, characteristics of the splicing variants, and homo/heterodimerization of RXFP1 in both normal physiological function and human diseases. We discuss the potential implications of these molecular features for developing therapeutics to restore relaxin/RXFP1 signaling and to harness relaxin's potential antifibrotic effects.

Results: Relaxin/RXFP1 signaling is important in both normal physiology and in human diseases. Reduced expression of RXFP1 in fibrotic lung and skin tissues surrenders both relaxin/RXFP1 signaling and their responsiveness to exogenous relaxin treatments. Alternative splicing and receptor dimerization are also important in regulating relaxin/RXFP1 signaling.

Conclusions: Understanding the molecular mechanisms that drive aberrant expression of RXFP1 in disease and the functional roles of alternative splicing and receptor dimerization will provide insight into therapeutic targets that may restore the relaxin responsiveness of fibrotic tissues.

Keywords: RXFP1; alternative splicing; fibrosis; relaxin.

Figure 1

Alternative splicing variants of RXFP1. The genomic structures are shown on the left. The functions of each splicing variant in relaxin binding, signaling, and interfering of wild‐type RXFP1 function are shown on the right. The designations from original reports for each alternative splicing variant are shown. Coding exons are shown in colors and noncoding exons are shown as gray boxes. The locations of novel premature stop codons are shown. (a) Wild‐type RXFP1 gene. Only exons were drawn based on their relative size. The coding exons for each protein domains are shown. (b) Genomic structures of three truncated N‐terminus RXFP1 splicing variants that retain the LDLa module. (c) Genomic structures of truncated N‐terminus RXFP1 that retain both LDLa module and linker domain. For the novel exons 6A and 15A in LGR7 are shown in red‐framed boxes. (d) Genomic structure of a truncated N‐terminus RXFP1 splicing variant, LGR7‐C, retains LDLa module, linker domain and majority of LRRs. (e) Genomic structures of two splicing variants resulted from in‐frame deletion. For the summary table, positive function is labeled as (✓), lack of function is labeled as (X), inconclusive findings in the literature is labeled as (??), and not analyzed is labeled as (N/A). Ref, cited references are: 1. Kern et al. (2008); 2. Scott et al. (2006); 3. Muda et al. (2005); 4. Kern and Bryant‐Greenwood (2009); 5. Hsu et al. (2000); 6. Scott et al. (2006). Abbreviations: LDLa, low‐density lipoprotein class A; LRR, leucine‐rich repeat