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.
- 1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (M.L.H., R.J.S.); Neuropeptides Division, Florey Institute of Neuroscience and Mental Health and Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia (R.A.D.B.); Neuroscience Drug Discovery, Janssen Research & Development, LLC, San Diego, California (S.W.S.); Immundiagnostik AG, Bensheim, Germany (T.B.D.); and Charité-University Medicine Berlin, Campus Mitte, Medical Clinic for Cardiology and Angiology, Berlin, Germany (T.B.D.).
- 2. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (M.L.H., R.J.S.); Neuropeptides Division, Florey Institute of Neuroscience and Mental Health and Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia (R.A.D.B.); Neuroscience Drug Discovery, Janssen Research & Development, LLC, San Diego, California (S.W.S.); Immundiagnostik AG, Bensheim, Germany (T.B.D.); and Charité-University Medicine Berlin, Campus Mitte, Medical Clinic for Cardiology and Angiology, Berlin, Germany (T.B.D.) [email protected].
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.