The lutropin/choriogonadotropin receptor (LHR), present on the cell surface of certain cells in the ovaries and testes, plays a critical role in reproductive physiology. Recent studies from our lab and others on the cloning of the cDNA for this receptor have shown that it is a member of the family of G protein-coupled receptors and thus contains the characteristic feature of seven membrane-spanning domains oriented with the C-terminus on the cytoplasmic face. Unlike many other G protein- coupled receptors, however, the LHR contains a large extracellular domain which we and others have shown to be sufficient for high affinity binding of hCG. The focus of the present grant is to continue some studies that have already begun and to initiate others that will yield information about the structure and function relationships of the LHR and in turn on the mechanism of action of the receptor. Specifically, the aims of the grant are to: A. Determine the sites of N-linked glycosylation on the rLHR and their role, if any, on signal transduction B. Continue studies on identifying regions of the rLHR which mediate hormone-occupied receptor internalization C. Identify regions of the rLHR involved in activating G proteins D. Investigate the mechanisms of rLHR activation The information learned from these studies will contribute to our understanding of G protein-coupled receptors in general (which are integral to various physiological systems) and more specifically will further our understanding of the role of this receptor in reproductive physiology. As such, it is anticipated that the results of these studies will aid us in the future in understanding, diagnosing, and treating certain forms of infertility, as well as in the design of novel contraceptive agents to suppress fertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD022196-13
Application #
2392383
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1990-05-01
Project End
1999-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
13
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Iowa
Department
Physiology
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Charmandari, E; Guan, R; Zhang, M et al. (2016) Misfolding Ectodomain Mutations of the Lutropin Receptor Increase Efficacy of Hormone Stimulation. Mol Endocrinol 30:62-76
Stilley, Julie A W; Christensen, Debora E; Dahlem, Kristin B et al. (2014) FSH receptor (FSHR) expression in human extragonadal reproductive tissues and the developing placenta, and the impact of its deletion on pregnancy in mice. Biol Reprod 91:74
Stilley, Julie A; Guan, Rongbin; Duffy, Diane M et al. (2014) Signaling through FSH receptors on human umbilical vein endothelial cells promotes angiogenesis. J Clin Endocrinol Metab 99:E813-20
Feng, Xiuyan; Zhang, Meilin; Guan, Rongbin et al. (2013) Heterodimerization between the lutropin and follitropin receptors is associated with an attenuation of hormone-dependent signaling. Endocrinology 154:3925-30
Segaloff, Deborah L (2012) Regulatory processes governing the cell surface expression of LH and FSH receptors. Subcell Biochem 63:113-29
Zhang, Meilin; Guan, Rongbin; Segaloff, Deborah L (2012) Revisiting and questioning functional rescue between dimerized LH receptor mutants. Mol Endocrinol 26:655-68
Newton, Claire L; Whay, Adele M; McArdle, Craig A et al. (2011) Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist. Proc Natl Acad Sci U S A 108:7172-6
Guan, Rongbin; Wu, Xueqing; Feng, Xiuyan et al. (2010) Structural determinants underlying constitutive dimerization of unoccupied human follitropin receptors. Cell Signal 22:247-56
Peltoketo, Hellevi; Strauss, Leena; Karjalainen, Riikka et al. (2010) Female mice expressing constitutively active mutants of FSH receptor present with a phenotype of premature follicle depletion and estrogen excess. Endocrinology 151:1872-83
Segaloff, Deborah L (2010) Constitutive activity of the lutropin receptor and its allosteric modulation by receptor heterodimerization. Methods Enzymol 484:231-52

Showing the most recent 10 out of 68 publications