Abstract
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.
Footnotes
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↵1 Abbreviations: RLN1, gene encoding H1 relaxin; RLN2, gene encoding H2 relaxin; H1 relaxin, human gene 1 relaxin; H2 relaxin, human gene 2 relaxin; H3 relaxin, human gene 3 relaxin; (species) relaxin-3, peptide corresponding to human gene 3 (H3) relaxin in other species; Ley-I-L, Leydig insulin-like peptide; INSL3, gene encoding insulin-like peptide 3; INSL4, gene encoding insulin-like peptide 4; INSL5, gene encoding insulin-like peptide 5; INSL6, gene encoding insulin-like peptide 6; RLF, relaxin-like factor; INSL3, insulin-like peptide 3; INSL4, insulin-like peptide 4; INSL5, insulinlike peptide 5; INSL6, insulin-like peptide 6; LGR, leucine-rich repeat-containing guanine nucleotide binding (G-protein)-coupled receptors; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thryroid-stimulating hormone; Great, G-protein coupled receptor affecting testis descent; LGR7, leucine-rich repeat-containing guanine nucleotide binding (G-protein)-coupled receptor 7; LGR8, leucine-rich repeat-containing guanine nucleotide binding (G-protein)-coupled receptor 8; GPCR, G-protein coupled receptor; GPCR135, G-protein coupled receptor 135 (orphan receptor nomenclature); GPCR142, G-protein coupled receptor 142 (orphan receptor nomenclature); RXFP1, relaxin family peptide receptor 1; RXFP2, relaxin family peptide receptor 2; RXFP3, relaxin family peptide receptor 3; RXFP4, relaxin family peptide receptor 4; RT-PCR, reverse transcription-polymerase chain reaction; PKA, protein kinase A; SFO, subfornical organ; OVLT, organum vasculosum of the lamina terminalis; ET1-32, first 32 amino acids of endothelin peptide; NO, nitric oxide; NOS, nitric-oxide synthase; THP-1, human monocytic cell line; LRR, leucine-rich repeat; LDLa, low-density lipoprotein class A; TM, transmembrane; PKC, protein kinase C; MAPK, mitogen-activated protein kinase; PDE, phosphodiesterase; HEK293, human embryonic kidney (cells); LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride; PI3-K, phosphatidyinositol 3 kinase; Erk1/2, extracellular signalling regulated kinase; GR, glucocorticoid receptor; RU486, 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one.
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This work was supported in part by a National Health and Medical Research Council (NH&MRC) block grant to the Howard Florey Institute (Reg Key 983001), NH&MRC project grants to R.A.D.B. and R.J.S. (300012) and R.I (349502), Australian Research Council Linkage Grant LP0211545 to R.J.S., and Grant Iv7/11 from the Deutsche Forschungsgemeinschaft to R.I.
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Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org.
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doi:10.1124/pr.58.1.9.
- The American Society for Pharmacology and Experimental Therapeutics
In this issue
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- Article
- Abstract
- I. Brief Historical Background of Relaxin Family Peptides and Their Receptors
- II. Receptor Distribution and Function
- III. Structure of Relaxin Family Peptides
- IV. Structure-Activity Relationships
- V. Binding of Relaxin and Relaxin Family Peptides
- VI. Relaxin Family Peptide Receptors
- VII. Functional Domains of Receptors for Relaxin Family Peptides
- VIII. Signaling Pathways Activated by Relaxin Family Peptides
- IX. Regulation of Relaxin Family Peptide Receptors
- X. Nomenclature Issues for Relaxin Family Peptides and Their Receptors
- Acknowledgments
- Footnotes
- References
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