Follicle-stimulating hormone glycoform interactions with the FSH receptor
Follicle-stimulating hormone (FSH) is a gonadotropic hormone produced by the ante-rior pituitary, which plays a major role in follicular development leading up to ovulation and spermatogenesis. FSH possesses two dissimilar subunits, α and β, like other members of the glycoprotein hormone family. Human FSH exists as a heterogeneous mixture of glycoforms, differing in the number and location of two β subunit N-glycans. FSH acts through its cog-nate receptor to initiate a series of physiological events required for granulosa cell prolifera-tion and differentiation in the ovary, as well as Sertoli cell function in the testis. Preliminary studies have documented thiazolidinone derivatives activate FSH receptors expressed in Chi-nese hamster ovarian (CHO) cells and rat granulosa cells, however, the mechanism of action for this compound is not yet determined. The objective of our studies is to extend the previ-ous investigations regarding one of these molecules, called compound 5, and study its ability to increase FSH/FSH receptor complex internalization rate. We believe that at least a portion of the increased FSH binding in the presence of Compound 5 results from increased internali-zation of the FSH-receptor complex. We analyzed the kinetics of FSH/FSH receptor complex endocytosis using 125I-hFSH21, 125I-hFSH24 and 125I-eFSH glycoform tracers in the presence and absence of Com-pound 5 using recombinant hFSHR-expressing CHO cells as a model system. We also per-formed modeling studies of Compound 5 interactions with the FSH receptor, which suggest-ed a potential binding site on the FSH receptor for this molecule, which was distinct from the large N-terminal extracellular domain. This study is the first report of increased internaliza-tion rate of FSH/FSH receptor complexes resulting from exposure to Compound 5.
Thesis (M.S.)--Wichita State University, Fairmount College of Liberal Arts and Sciences, Dept. of Biological Sciences