FSH RECEPTOR--STRUCTURE AND FUNCTION

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The FSH receptor (FSH-R), present on testicular Sertoli cells and on ovarian granulosa cells, binds circulating FSH and transduces that binding into the activation of a Gs protein. Physiologically, the response of these target cells to circulating FSH is critical for normal spermatogenesis in the male and for follicular development in the female. From the cloning of the cDNA for the rat FSH-R, it is now known that this receptor is a single polypepeptide which consists of a large N-terminal extracellular domain (which contains three sites for potential N-linked glycosylation) attached to a C-terminal half which is homologous to other G protein-coupled receptors (and thus presumably spans the plasma membrane seven times). Thus, the overall structural organization of the FSH-R is similar to that observed in the LH/CG and TSH receptors. Together these three glycoprotein hormone receptors appear to comprise a unique subgroup within the family of G protein-coupled receptors in that they contain large extracellular domains. Importantly, the cloning of the cDNA for the FSH-R now allows investigators to pursue more detailed questions pertaining to the structure and mechanism of action of this receptor. Specifically, the specific aims we propose are the following: (1) Express a cDNA encoding the extracellular domain of the FSH-R in mammalian cells. Characterize the truncated receptor and verify that this region confers high affinity binding and binding specificity. (2) Determine the role of glycosylation of the extracellular domain of the FSH-R. (3) Establish a system for the overexpression of FSH-R and the extracellular domain of the FSH-R and characterize the proteins thus expressed. (4) Determine those amino acids involved in hormone binding and receptor-Gs protein coupling and activation. Although the results of these studies alone will provide novel information concerning the FSH-R, they will also provide the groundwork for more detailed studies in the future. It is also anticipated that the basic knowledge learned from these studies will be valuable towards understanding and perhaps controlling fertility and infertility.