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IUPHAR Nomenclature Report |
Howard Florey Institute, University of Melbourne, Melbourne, Victoria, Australia (R.A.B.); School of Molecular and Biomedical Science, The University of Adelaide, South Australia, Australia (R.I.); Department of Biological Sciences, Colorado State University, Fort Collins, Colorado (B.M.S.); Department of Molecular and Integrative Physiology and College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois (O.D.S.); Department of Pharmacology, Monash University, Clayton, Victoria, Australia (R.J.S.)
Abstract
Abstract I. Brief Historical Background of Relaxin Family Peptides and Their Receptors II. Receptor Distribution and Function A. Reproductive Tissues B. Brain C. Cardiovascular and Renal Systems D. Other Sites of Action of Relaxin Family Peptides E. Roles of Relaxin Family Peptides Determined from Studies in Receptor Knockout Mice III. Structure of Relaxin Family Peptides A. Structural Features of Relaxin B. Structural Features of Other Relaxin Family Peptides IV. Structure-Activity Relationships A. Relaxin B. INSL3 V. Binding of Relaxin and Relaxin Family Peptides A. Relaxin Binding B. Binding of Other Relaxin Family Peptides VI. Relaxin Family Peptide Receptors A. RXFP1 and RXFP2 B. RXFP3 and RXFP4 VII. Functional Domains of Receptors for Relaxin Family Peptides A. General Features of Leucine-Rich Repeat-Containing Receptors B. Functional Domains of RXFP1 and RXFP2 (LGR7 and LGR8) C. Functional Domains of RXFP3 and RXFP4 (GPCR135 and GPCR142) VIII. Signaling Pathways Activated by Relaxin Family Peptides A. Signaling in Response to Relaxin B. Signaling in Response to Other Relaxin Family Peptides IX. Regulation of Relaxin Family Peptide Receptors X. Nomenclature Issues for Relaxin Family Peptides and Their Receptors
Although the hormone relaxin was discovered 80 years ago, only in the past 5 years have the receptors for relaxin and three other receptors that respond to related peptides been identified with all four receptors being G-protein-coupled receptors. In this review it is suggested that the receptors for relaxin (LGR7) and those for the related peptides insulin-like peptide 3 (LGR8), relaxin-3 (GPCR135), and insulin-like peptide 5 (LGPCR142) be named the relaxin family peptide receptors 1 through 4 (RXFP1-4). RXFP1 and RXFP2 are leucine-rich repeat-containing G-protein-coupled receptors with complex binding characteristics involving both the large ectodomain and the transmembrane loops. RXFP1 activates adenylate cyclase, protein kinase A, protein kinase C, phosphatidylinositol 3-kinase, and extracellular signaling regulated kinase (Erk1/2) and also interacts with nitric oxide signaling. RXFP2 activates adenylate cyclase in recombinant systems, but physiological responses are sensitive to pertussis toxin. RXFP3 and RXFP4 resemble more conventional peptide liganded receptors and both inhibit adenylate cyclase, and in addition RXFP3 activates Erk1/2 signaling. Physiological studies and examination of the phenotypes of transgenic mice have established that relaxin has roles as a reproductive hormone involved in uterine relaxation (some species), reproductive tissue growth, and collagen remodeling but also in the cardiovascular and renal systems and in the brain. The connective tissue remodeling properties of relaxin acting at RXFP1 receptors have potential for the development of agents effective for the treatment of cardiac and renal fibrosis, asthma, and scleroderma and for orthodontic remodelling. Agents acting at RXFP2 receptors may be useful for the treatment of cryptorchidism and infertility, whereas antagonists may be used as contraceptives. The brain distribution of RXFP3 receptors suggests that actions at these receptors have the potential for the development of antianxiety and antiobesity drugs.
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