title: 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.
abstract: 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.
authors.affiliation: 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.).
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Halls
authors.affiliation: 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.).
authors.forename: Ross A D
authors.initials: RA
authors.lastname: Bathgate
authors.affiliation: 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.).
authors.forename: Steve W
authors.initials: SW
authors.lastname: Sutton
authors.affiliation: 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.).
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Dschietzig
authors.affiliation: 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.) roger.summers@monash.edu.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Summers
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology*; D006801:Humans; D007390:International Agencies; D008024:Ligands; D008958:Models, Molecular; D010600:Pharmacology / Q000639:trends; D010601:Pharmacology, Clinical / Q000639:trends; D020033:Protein Isoforms / Q000819:agonists / Q000737:chemistry / Q000145:classification / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D018000:Receptors, Peptide / Q000819:agonists / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D012065:Relaxin / Q000819:agonists / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015290:Second Messenger Systems; D012958:Societies, Scientific; D009626:Terminology as Topic
chemical_list: D008024:Ligands; D020033:Protein Isoforms; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; C033395:relaxin receptors; D012065:Relaxin; D000242:Cyclic AMP