Relaxin family peptide receptors


Relaxin family peptide receptors (RXFP) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are heterodimeric peptide hormones structurally related to insulin: relaxin-1, relaxin, relaxin-3 (also known as INSL7), insulin-like peptide 3 (INSL3) and INSL5. Species homologues of relaxin have distinct pharmacology and relaxin interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [1]. relaxin-3 is the ligand for RXFP3 but it also binds to RXFP1 and RXFP4 and has differential affinity for RXFP2 between species [2]. INSL5 is the ligand for RXFP4 but is a weak antagonist of RXFP3. relaxin and INSL3 have multiple complex binding interactions with RXFP1 [3] and RXFP2 [4] which direct the N-terminal LDLa modules of the receptors together with a linker domain to act as a tethered ligand to direct receptor signaling [5]. INSL5 and relaxin-3 interact with their receptors using distinct residues in their B-chains for binding, and activation, respectively [6,7].


  1. Scott DJ, Layfield S, Riesewijk A, et al. Characterization of the mouse and rat relaxin receptors. Ann N Y Acad Sci 2005;1041:8-12.
  2. Scott DJ, Fu P, Shen PJ, et al. Characterization of the rat INSL3 receptor. Ann N Y Acad Sci 2005;1041:13-6.
  3. Sethi A, Bruell S, Patil N, et al. The complex binding mode of the peptide hormone H2 relaxin to its receptor RXFP1. Nat Commun 2016;7:11344.
  4. Hoare BL, Bruell S, Sethi A, et al. Multi-Component Mechanism of H2 Relaxin Binding to RXFP1 through NanoBRET Kinetic Analysis. iScience 2019;11:93-113.
  5. Scott DJ, Layfield S, Yan Y, et al. 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 2006;281:34942-54.
  6. Wong LLL, Scott DJ, Hossain MA, et al. Distinct but overlapping binding sites of agonist and antagonist at the relaxin family peptide 3 (RXFP3) receptor. J Biol Chem 2018;293:15777-15789.
  7. Hu MJ, Wei D, Shao XX, et al. Interaction mechanism of insulin-like peptide 5 with relaxin family peptide receptor 4. Arch Biochem Biophys 2017;619:27-34.
Excerpt from IUPHAR/BPS Guide to Pharmacology
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