ECE2006 Symposia Novel peptides in reproduction (4 abstracts)
A genomic analysis of polypeptide ligands and receptors: the example of relaxin and LGR families
A Hsueh , K Kawamura , C Luo , S Mazerbourg , J Kumagai , O Avsian-Kretchmer , R Rauch , I Ben-Shlomo & S Yu Hsu
Division of Reproductive Biology, Stanford University, Stanford, CA, USA.
The availability of genome sequences from humans and multiple model organisms has facilitated the identification of many human plasma membrane receptor families and allowed the analysis of their phylogeny. We traced the evolution of known families of human plasma membrane receptors for inclusion in the Human Plasma Membrane Receptome database at http://receptome.stanford.edu (Science STKE. 2003). Using an evolutionary approach, we identified new polypeptide hormones and receptors. Because of the coevolution of polypeptide ligands and their cognate receptors, analysis of human genomic sequences allows one to predict the pairing of these elements. Initially, we identified a group of five orphan LGRs (leucine-rich repeat-containing G protein-coupled receptors) homologous to LH, FSH, and TSH receptors (Mol Endocrinol 1998, 1990). Matching the polypeptide hormones and receptors led to the finding of a new glycoprotein hormone as an agonistic ligand for the TSH receptor (J Clin Invest., 2002). In addition, the receptor for the classic hormone, relaxin, was identified as LGR7 (Science 2002) whereas INSL3 was found to be the specific ligand for LGR8 (JBC 2002). We investigated the expression of the INSL3 receptor LGR8 in male and female gonads. We found that LH stimulates INSL3 transcripts in ovarian theca and testicular Leydig cells. INSL3, in turn, binds LGR8 expressed in germ cells to initiate meiotic progression of arrested oocytes in preovulatory follicles and to suppress male germ cell apoptosis (PNAS 2004). Thus, genomic analysis of the evolution of polypeptide ligand and receptor gene families provides a new paradigm for future identification and matching of novel ligands and receptors.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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