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Science 295 (5555): 671-674

Copyright © 2002 by the American Association for the Advancement of Science

Activation of Orphan Receptors by the Hormone Relaxin

Sheau Yu Hsu,1 Koji Nakabayashi,1 Shinya Nishi,1 Jin Kumagai,1 Masataka Kudo,1 O. David Sherwood,2 Aaron J. W. Hsueh1*

Relaxin is a hormone important for the growth and remodeling of reproductive and other tissues during pregnancy. Although binding sites for relaxin are widely distributed, the nature of its receptor has been elusive. Here, we demonstrate that two orphan heterotrimeric guanine nucleotide binding protein (G protein)-coupled receptors, LGR7 and LGR8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (cAMP)-dependent pathway distinct from that of the structurally related insulin and insulin-like growth factor family ligand. Treatment of antepartum mice with the soluble ligand-binding region of LGR7 caused parturition delay. The wide and divergent distribution of the two relaxin receptors implicates their roles in reproductive, brain, renal, cardiovascular, and other functions.

1 Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
2 Department of Molecular and Integrative Physiology, University of Illinois, Urbana-Champaign, IL 61801, USA.
*   To whom correspondence should be addressed. E-mail: aaron.hsueh{at}stanford.edu



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Am J Physiol Regulatory Integrative Comp Physiol 287, R250-R261
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Disparate effects of relaxin and TGF{beta}1: relaxin increases, but TGF{beta}1 inhibits, the relaxin receptor and the production of IGFBP-1 in human endometrial stromal/decidual cells.
J. Mazella, M. Tang, and L. Tseng (2004)
Hum. Reprod. 19, 1513-1518
   Abstract »    Full Text »    PDF »
Paracrine regulation of mammalian oocyte maturation and male germ cell survival.
K. Kawamura, J. Kumagai, S. Sudo, S.-Y. Chun, M. Pisarska, H. Morita, J. Toppari, P. Fu, J. D. Wade, R. A. D. Bathgate, et al. (2004)
PNAS 101, 7323-7328
   Abstract »    Full Text »    PDF »
Intermedin Is a Calcitonin/Calcitonin Gene-related Peptide Family Peptide Acting through the Calcitonin Receptor-like Receptor/Receptor Activity-modifying Protein Receptor Complexes.
J. Roh, C. L. Chang, A. Bhalla, C. Klein, and S. Y. T. Hsu (2004)
J. Biol. Chem. 279, 7264-7274
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Gene expression pattern and immunoreactive protein localization of LGR7 receptor in human endometrium throughout the menstrual cycle.
J. J. Luna, A. Riesewijk, J. A. Horcajadas, R. d. van Os, F. Dominguez, S. Mosselman, A. Pellicer, and C. Simon (2004)
Mol. Hum. Reprod. 10, 85-90
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Identification and Structural Characterization of the Neuronal Luteinizing Hormone Receptor Associated with Sensory Systems.
P. M. Apaja, K. T. Harju, J. T. Aatsinki, U. E. Petaja-Repo, and H. J. Rajaniemi (2004)
J. Biol. Chem. 279, 1899-1906
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Impaired Nipple Development and Parturition in LGR7 Knockout Mice.
M. A. M. Krajnc-Franken, A. J. M. van Disseldorp, J. E. Koenders, S. Mosselman, M. van Duin, and J. A. Gossen (2004)
Mol. Cell. Biol. 24, 687-696
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Identification of Relaxin-3/INSL7 as an Endogenous Ligand for the Orphan G-protein-coupled Receptor GPCR135.
C. Liu, E. Eriste, S. Sutton, J. Chen, B. Roland, C. Kuei, N. Farmer, H. Jornvall, R. Sillard, and T. W. Lovenberg (2003)
J. Biol. Chem. 278, 50754-50764
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Identification of Relaxin-3/INSL7 as a Ligand for GPCR142.
C. Liu, J. Chen, S. Sutton, B. Roland, C. Kuei, N. Farmer, R. Sillard, and T. W. Lovenberg (2003)
J. Biol. Chem. 278, 50765-50770
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N-terminal pro B type natriuretic peptide, but not the new putative cardiac hormone relaxin, predicts prognosis in patients with chronic heart failure.
C Fisher, C Berry, L Blue, J J Morton, and J McMurray (2003)
Heart 89, 879-881
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Functional Characterization of Human Receptors for Short Chain Fatty Acids and Their Role in Polymorphonuclear Cell Activation.
E. Le Poul, C. Loison, S. Struyf, J.-Y. Springael, V. Lannoy, M.-E. Decobecq, S. Brezillon, V. Dupriez, G. Vassart, J. Van Damme, et al. (2003)
J. Biol. Chem. 278, 25481-25489
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Signaling Receptome: A Genomic and Evolutionary Perspective of Plasma Membrane Receptors Involved in Signal Transduction.
I. Ben-Shlomo, S. Yu Hsu, R. Rauch, H. W. Kowalski, and A. J. W. Hsueh (2003)
Sci. STKE 2003, re9
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INSL3 Ligand-Receptor System in the Equine Testis.
T. Klonisch, K. Steger, A. Kehlen, W. R. Allen, C. Froehlich, J. Kauffold, M. Bergmann, and S. Hombach-Klonisch (2003)
Biol Reprod 68, 1975-1981
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The molecular basis of cryptorchidism.
R. Ivell and S. Hartung (2003)
Mol. Hum. Reprod. 9, 175-181
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daf-28 encodes a C. elegans insulin superfamily member that is regulated by environmental cues and acts in the DAF-2 signaling pathway.
W. Li, S. G. Kennedy, and G. Ruvkun (2003)
Genes & Dev. 17, 844-858
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H3 Relaxin Is a Specific Ligand for LGR7 and Activates the Receptor by Interacting with Both the Ectodomain and the Exoloop 2.
S. Sudo, J. Kumagai, S. Nishi, S. Layfield, T. Ferraro, R. A. D. Bathgate, and A. J. W. Hsueh (2003)
J. Biol. Chem. 278, 7855-7862
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Relaxin, a Pregnancy Hormone, Is a Functional Endothelin-1 Antagonist: Attenuation of Endothelin-1-Mediated Vasoconstriction by Stimulation of Endothelin Type-B Receptor Expression via ERK-1/2 and Nuclear Factor-{kappa}B.
T. Dschietzig, C. Bartsch, C. Richter, M. Laule, G. Baumann, and K. Stangl (2003)
Circ. Res. 92, 32-40
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Identification of Natural Ligands for the Orphan G Protein-coupled Receptors GPR7 and GPR8.
S. Brezillon, V. Lannoy, J.-D. Franssen, E. Le Poul, V. Dupriez, J. Lucchetti, M. Detheux, and M. Parmentier (2003)
J. Biol. Chem. 278, 776-783
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Relaxin Stimulates Bronchial Epithelial Cell PKA Activation, Migration, and Ciliary Beating.
T. A. Wyatt, J. H. Sisson, M. A. Forget, R. G. Bennett, F. G. Hamel, and J. R. Spurzem (2002)
Experimental Biology and Medicine 227, 1047-1053
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The role of insulin 3, testosterone, Mullerian inhibiting substance and relaxin in rat gubernacular growth.
Y. Kubota, C. Temelcos, R.A.D. Bathgate, K.J. Smith, D. Scott, C. Zhao, and J.M. Hutson (2002)
Mol. Hum. Reprod. 8, 900-905
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Mutations of the GREAT gene cause cryptorchidism.
I. P. Gorlov, A. Kamat, N. V. Bogatcheva, E. Jones, D. J. Lamb, A. Truong, C. E. Bishop, K. McElreavey, and A. I. Agoulnik (2002)
Hum. Mol. Genet. 11, 2309-2318
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Relaxin enhances in-vitro invasiveness of breast cancer cell lines by up-regulation of matrix metalloproteases.
C. Binder, Th. Hagemann, B. Husen, M. Schulz, and A. Einspanier (2002)
Mol. Hum. Reprod. 8, 789-796
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Reproductive Biology of the Relaxin-Like Factor (RLF/INSL3).
R. Ivell and R. A.D. Bathgate (2002)
Biol Reprod 67, 699-705
   Abstract »    Full Text »    PDF »

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