Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Biol. Chem. 281 (46): 34942-34954

© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

Characterization of Novel Splice Variants of LGR7 and LGR8 Reveals That Receptor Signaling Is Mediated by Their Unique Low Density Lipoprotein Class A Modules*

Daniel J. Scott{ddagger}§1, Sharon Layfield{ddagger}, Yan Yan{ddagger}, Satoko Sudo||, Aaron J. W. Hsueh||, Geoffrey W. Tregear{ddagger}§, , and Ross A. D. Bathgate{ddagger}§2

{ddagger}Howard Florey Institute and §Department of Biochemistry and Molecular Biology, University of Melbourne, Victoria 3010, Australia, the ||Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305-5317, and the National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing 100871, China

Abstract: The relaxin and insulin-like peptide 3 receptors, LGR7 and LGR8, respectively, are unique members of the leucine-rich repeat-containing G-protein-coupled receptor (LGR) family, because they possess an N-terminal motif with homology to the low density lipoprotein class A (LDLa) modules. By characterizing several LGR7 and LGR8 splice variants, we have revealed that the LDLa module directs ligand-activated cAMP signaling. The LGR8-short variant encodes an LGR8 receptor lacking the LDLa module, whereas LGR7-truncate, LGR7-truncate-2, and LGR7-truncate-3 all encode truncated secreted proteins retaining the LGR7 LDLa module. LGR8-short and an engineered LGR7 variant missing its LDLa module, LGR7-short, bound to their respective ligands with high affinity but lost their ability to signal via stimulation of intracellular cAMP accumulation. Conversely, secreted LGR7-truncate protein with the LDLa module was able to block relaxin-induced LGR7 cAMP signaling and did so without compromising the ability of LGR7 to bind to relaxin or be expressed on the cell membrane. Although the LDLa module of LGR7 was N-glycosylated at position Asn-14, an LGR7 N14Q mutant retained relaxin binding affinity and cAMP signaling, implying that glycosylation is not essential for optimal LDLa function. Using real-time PCR, the expression of mouse LGR7-truncate was detected to be high in, and specific to, the uterus of pregnant mice. The differential expression and evolutionary conservation of LGR7-truncate further suggests that it may also play an important role in vivo. This study highlights the essential role of the LDLa module in LGR7 and LGR8 function and introduces a novel model of GPCR regulation.

Received for publication March 23, 2006. Revision received July 24, 2006.

* This work was supported in part by an Australian National Health and Medical Research Council Project grant (#30012 to R. A. D. B. and G. W. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Recipient of an Australian Postgraduate Award.

2 To whom correspondence should be addressed. Tel.: 61-3-8344-5648; Fax: 61-3-9347-0446; E-mail: r.bathgate{at}

Dynamics of insulin-like factor 3 and its receptor expression in boar testes.
I. Minagawa, D. Sagata, A. M. Pitia, H. Kohriki, M. Shibata, H. Sasada, Y. Hasegawa, and T. Kohsaka (2014)
J. Endocrinol. 220, 247-261
   Abstract »    Full Text »    PDF »
The Relaxin Receptor (RXFP1) Utilizes Hydrophobic Moieties on a Signaling Surface of Its N-terminal Low Density Lipoprotein Class A Module to Mediate Receptor Activation.
R. C. K. Kong, E. J. Petrie, B. Mohanty, J. Ling, J. C. Y. Lee, P. R. Gooley, and R. A. D. Bathgate (2013)
J. Biol. Chem. 288, 28138-28151
   Abstract »    Full Text »    PDF »
Identification of Small-Molecule Agonists of Human Relaxin Family Receptor 1 (RXFP1) by Using a Homogenous Cell-Based cAMP Assay.
C. Z. Chen, N. Southall, J. Xiao, J. J. Marugan, M. Ferrer, X. Hu, R. E. Jones, S. Feng, I. U. Agoulnik, W. Zheng, et al. (2013)
J Biomol Screen 18, 670-677
   Abstract »    Full Text »    PDF »
Relaxin Family Peptides and Their Receptors.
R. A. D. Bathgate, M. L. Halls, E. T. van der Westhuizen, G. E. Callander, M. Kocan, and R. J. Summers (2013)
Physiol Rev 93, 405-480
   Abstract »    Full Text »    PDF »
Identification of Key Residues Essential for the Structural Fold and Receptor Selectivity within the A-chain of Human Gene-2 (H2) Relaxin.
L. J. Chan, K. J. Rosengren, S. L. Layfield, R. A. D. Bathgate, F. Separovic, C. S. Samuel, M. A. Hossain, and J. D. Wade (2012)
J. Biol. Chem. 287, 41152-41164
   Abstract »    Full Text »    PDF »
Relaxin mediates uterine artery compliance during pregnancy and increases uterine blood flow.
L. A. Vodstrcil, M. Tare, J. Novak, N. Dragomir, R. J. Ramirez, M. E. Wlodek, K. P. Conrad, and L. J. Parry (2012)
FASEB J 26, 4035-4044
   Abstract »    Full Text »    PDF »
The Minimal Active Structure of Human Relaxin-2.
M. A. Hossain, K. J. Rosengren, C. S. Samuel, F. Shabanpoor, L. J. Chan, R. A. D. Bathgate, and J. D. Wade (2011)
J. Biol. Chem. 286, 37555-37565
   Abstract »    Full Text »    PDF »
Relaxin family peptides in the male reproductive system--a critical appraisal.
R. Ivell, M. Kotula-Balak, D. Glynn, K. Heng, and R. Anand-Ivell (2011)
Mol. Hum. Reprod. 17, 71-84
   Abstract »    Full Text »    PDF »
Evidence for expression of relaxin hormone-receptor system in the boar testis.
S. Kato, Siqin, I. Minagawa, T. Aoshima, D. Sagata, H. Konishi, K. Yogo, T. Kawarasaki, H. Sasada, H. Tomogane, et al. (2010)
J. Endocrinol. 207, 135-149
   Abstract »    Full Text »    PDF »
Decreased Expression of the Rat Myometrial Relaxin Receptor (RXFP1) in Late Pregnancy Is Partially Mediated by the Presence of the Conceptus.
L. A. Vodstrcil, O. Shynlova, J. W. Verlander, M. E. Wlodek, and L. J. Parry (2010)
Biol Reprod 83, 818-824
   Abstract »    Full Text »    PDF »
Biology of insulin-like factor 3 in human reproduction.
R. Ivell and R. Anand-Ivell (2009)
Hum. Reprod. Update 15, 463-476
   Abstract »    Full Text »    PDF »
Prolonged RXFP1 and RXFP2 signaling can be explained by poor internalization and a lack of {beta}-arrestin recruitment.
G. E. Callander, W. G. Thomas, and R. A. D. Bathgate (2009)
Am J Physiol Cell Physiol 296, C1058-C1066
   Abstract »    Full Text »    PDF »
The A-chain of Human Relaxin Family Peptides Has Distinct Roles in the Binding and Activation of the Different Relaxin Family Peptide Receptors.
M. A. Hossain, K. J. Rosengren, L. M. Haugaard-Jonsson, S. Zhang, S. Layfield, T. Ferraro, N. L. Daly, G. W. Tregear, J. D. Wade, and R. A. D. Bathgate (2008)
J. Biol. Chem. 283, 17287-17297
   Abstract »    Full Text »    PDF »
The NMR Solution Structure of the Relaxin (RXFP1) Receptor Lipoprotein Receptor Class A Module and Identification of Key Residues in the N-terminal Region of the Module That Mediate Receptor Activation.
E. J. Hopkins, S. Layfield, T. Ferraro, R. A. D. Bathgate, and P. R. Gooley (2007)
J. Biol. Chem. 282, 4172-4184
   Abstract »    Full Text »    PDF »
Comparison of Signaling Pathways Activated by the Relaxin Family Peptide Receptors, RXFP1 and RXFP2, Using Reporter Genes.
M. L. Halls, R. A. D. Bathgate, and R. J. Summers (2007)
J. Pharmacol. Exp. Ther. 320, 281-290
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882