Halls Michelle L, Bathgate Ross A D, Sutton Steve W, Dschietzig Thomas B, Summers Roger J
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.).
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.)
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.
松弛素、胰岛素样肽3（INSL3）、松弛素-3和INSL5分别是松弛素家族肽（RXFP）受体1-4的同源配体。RXFP1激活多效性信号通路，包括促进高敏信号传导的信号体蛋白复合物；与Gα(s)、Gα(i)和Gα(o)蛋白偶联；与糖皮质激素受体相互作用；以及形成具有独特药理特性的异源寡聚体。除了与松弛素相关的配体外，RXFP1还可被C1q-肿瘤坏死因子相关蛋白8和小分子激动剂（如ML290 [2-异丙氧基-N-(2-(3-(三氟甲基磺酰基)phenylcarbamoyl)phenyl)苯甲酰胺]）变构激活。RXFP2仅激活与Gα(s)和Gα(o)偶联的信号通路。松弛素-3主要是一种神经肽，其同源受体RXFP3是治疗抑郁症、焦虑症和自闭症的靶点。多种肽类激动剂、拮抗剂、偏向激动剂和变构调节剂作用于RXFP3。RXFP3和相关的RXFP4均与Gα(i)/Gα(o)蛋白偶联。INSL5具有肠促胰岛素的特性；它从肠道分泌，具有促食欲作用。RXFP4在肠道、脂肪组织和β胰岛中的表达，以及INSL5或RXFP4基因敲除小鼠中受损的糖耐量表明其具有代谢作用。本综述重点介绍了过去5年我们对RXFP受体的认识取得的诸多进展、它们的信号转导机制以及靶向RXFP1-4的新型化合物的研发情况、该领域面临的挑战以及新疗法的当前前景。
