The lutropin/choriogonadotropin receptor (LHR) and follitropin receptor (FSHR), collectively termed the gonadotropin receptors, are members of the superfamily of G protein-coupled receptors (GPCRs). The pivotal importance of the gonadotropin receptors in reproductive physiology is underscored by the recent discoveries of pathologies associated with naturally occurring mutations of their genes. For example, many cases of gonadotropin-independent precocious puberty have been found to be attributable to mutations within the hLHR gene causing the hLHR to be constitutively active (i.e., active in the absence of hormone). Interestingly, when the equivalent mutations are introduced into the structurally similar hFSH constitutive activation is not necessarily observed. The studies proposed herein are a continuation of ongoing studies on the structure and function of the gonadotropin receptors, with a particular emphasis on understanding their mechanism of activation.
The aims of this proposal are to: 1. Determine if the ligand-independent activated state(s) of the hLHR are distinct from the agonist-dependent activated state of the hLHR. 2. Determine the mechanisms for the apparent resistance of the hFSHR to mutation-induced ligand-independent activation. 3. Determine the intrinsic activities of the wild-type gonadotropin receptors, activating mutants, and signaling- impaired mutants utilizing a reconstitution assay system consisting of purified receptor and purified Gs. 4. Investigate the possible agonist-dependent self-association of the gonadotropin receptors and whether this self-association is required for receptor activation. The results of these studies will contribute not only to our general understanding of GPCRs, but will also give us greater insights into reproductive physiology. Long term goals of research in this area include the ability to better understand, diagnose, and correct reproductive disorders.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Biochemical Endocrinology Study Section (BCE)
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Yoshinaga, Koji
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University of Iowa
Schools of Medicine
Iowa City
United States
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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

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