Human follitropin, also known as follicle stimulating hormone (hFSH), is an anterior pituitary glycoprotein hormone that stimulates spermatogenesis, the production of sperm, in males and the maturation of ovarian follicles and egg development in females. Follitropin receptors (hFSHR) can be found in granulosa cells in females and Sertoli cells in males. hFSH binds to the concave side of hFSHR in the membranes of these cells to induce signal transduction pathways, in which the induction of the second messenger cAMP is vital. hFSHR is a g protein-coupled receptor; it is often found in structures embedded into the plasma membrane called lipid rafts and caveolae. Lipid rafts and caveolae are rigid areas within the plasma membrane that compartmentalize the structures needed for specific functions; this compartmentalization greatly increases the efficiency of the cell to respond to extracellular signals. The hFSH receptor contains an extracellular and intracellular domain; the intracellular domain contains seven transmembrane ⍺-helices. Through previous research, mutations in intraloop three of the hFSHR have been shown to decrease signal transduction via decreased cAMP induction. Other mutations have been shown to impede FSH binding. This demonstrates that mutations in the hFSH receptor may lead to infertility in both females and males because mutations could result in a decline in follicular development or spermatogenesis. Follitropin is often used as a treatment for infertility however it cannot be effective if there is a mutation in the FSH receptor which makes it impossible for follitropin to bind or for a signal transduction pathway to respond.
This research is focused on the effects of a specific portion of the follitropin receptor in transmembrane domain four where a sequence thought to be involved in lipid raft residency is located. To test the effect of the mutations a cell line is being transfected with DNA coding for various mutant forms of hFSHR. Cells will then be treated with hFSH and signaling protein activation will be measured by western blot analysis. The activity of the mutant receptors will be compared to the wild type (normal sequence) receptor. The eventual goal of this research is to gain a better understanding of the structure-function relationship of the hFSHR to develop new approaches to treating infertility.