It is important that we understand how follicle-stimulating hormone (FSH) regulates its receptor in ovarian granulosa cells become hormone analogs and drugs that affect follicular development via the FSH receptor (FSHR) are being developed to provide health care professionals with better tools to control ovarian function and fertility. The overall objective of this project is to determine how the plasma membrane levels of FSHR are regulated by FSH in granulosa cells in vitro. The direct effects of FSH on the synthesis and turnover of the FSHR protein or mRNA have not been determined for any species so we do not have a precise knowledge of how FSH affects FSHR. The pig is an excellent model for studying the FSHR because it is possible to easily obtain large quantities of immature granulosa cells without having to resort to estrogen priming. Based on our findings and those of other investigators we hypothesize that FSH, via cAMP-dependent mechanisms, promotes the synthesis of FSHR via an increase in FSHR mRNA. We hypothesize further that his up-regulation is modulated simultaneously by a long-term, FSH- induced decrease in FSH-binding capacity that occurs both transient, reversible inactivation and by sequestration and/or internalization. Using cultured porcine granulosa cells we propose to determine, first, how FSH regulates FSHR mRNA levels, second, if exposure of FSHR results, either directly or indirectly, in alteration FSHR, third, how FSH affects the rates of sequestration and internalization of FSHR, fourth, if mutation of consensus internalization sequences alters the rate of internalization of FSHR, and fifth, what roles beta-arrestin and dynamin play in sequestration and internalization of FSHR. The results of these studies will facilitate development of methods to increase fertility and other species by elucidating how the FSH receptor is regulated by FSH.
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