International Union of Basic and Clinical Pharmacology. XCV. Recent advances in the understanding of the pharmacology and biological roles of relaxin family peptide receptors 1-4, the receptors for relaxin family peptides

Pharmacol Rev. 2015;67(2):389-440. doi: 10.1124/pr.114.009472.


Relaxin, insulin-like peptide 3 (INSL3), relaxin-3, and INSL5 are the cognate ligands for the relaxin family peptide (RXFP) receptors 1-4, respectively. RXFP1 activates pleiotropic signaling pathways including the signalosome protein complex that facilitates high-sensitivity signaling; coupling to Gα(s), Gα(i), and Gα(o) proteins; interaction with glucocorticoid receptors; and the formation of hetero-oligomers with distinctive pharmacological properties. In addition to relaxin-related ligands, RXFP1 is activated by Clq-tumor necrosis factor-related protein 8 and by small-molecular-weight agonists, such as ML290 [2-isopropoxy-N-(2-(3-(trifluoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide], that act allosterically. RXFP2 activates only the Gα(s)- and Gα(o)-coupled pathways. Relaxin-3 is primarily a neuropeptide, and its cognate receptor RXFP3 is a target for the treatment of depression, anxiety, and autism. A variety of peptide agonists, antagonists, biased agonists, and an allosteric modulator target RXFP3. Both RXFP3 and the related RXFP4 couple to Gα(i)/Gα(o) proteins. INSL5 has the properties of an incretin; it is secreted from the gut and is orexigenic. The expression of RXFP4 in gut, adipose tissue, and β-islets together with compromised glucose tolerance in INSL5 or RXFP4 knockout mice suggests a metabolic role. This review focuses on the many advances in our understanding of RXFP receptors in the last 5 years, their signal transduction mechanisms, the development of novel compounds that target RXFP1-4, the challenges facing the field, and current prospects for new therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Allosteric Regulation
  • Animals
  • Cell Membrane / enzymology
  • Cell Membrane / metabolism
  • Cyclic AMP / physiology*
  • Humans
  • International Agencies
  • Ligands
  • Models, Molecular*
  • Pharmacology / trends
  • Pharmacology, Clinical / trends
  • Protein Isoforms / agonists
  • Protein Isoforms / chemistry
  • Protein Isoforms / classification
  • Protein Isoforms / metabolism
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / classification
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Peptide / agonists
  • Receptors, Peptide / chemistry
  • Receptors, Peptide / classification
  • Receptors, Peptide / metabolism*
  • Relaxin / agonists
  • Relaxin / analogs & derivatives
  • Relaxin / antagonists & inhibitors
  • Relaxin / metabolism*
  • Second Messenger Systems*
  • Societies, Scientific
  • Terminology as Topic


  • Ligands
  • Protein Isoforms
  • Receptors, G-Protein-Coupled
  • Receptors, Peptide
  • relaxin receptors
  • Relaxin
  • Cyclic AMP