One of the fundamental processes by which hormone action is regulated is by preventing the interaction of the hormone-receptor complex with the effector system. This phenomenon, typically referred to as """"""""desensitization"""""""" has a rapid onset and occurs without changes in the number of hormone receptors. The studies proposed in this application take advantage of the knowledge and reagents gained by the recent cloning and functional expression of a cDNA encoding for the rat follitropin (FSH) receptor to elucidate the molecular basis of the desensitization of FSH responses. We will establish and characterize a simple experimental system to study the desensitization of FSH responses and we will use this system to identify and characterize potential modifications of the FSH receptor that may be involved in the process of desensitization. Once a given receptor modification is identified, its potential importance to the process of desensitization will be documented by functional analysis of FSH receptor mutants prepared by site-directed mutagenesis. Finally, experiments will be initiated to isolate and characterize the enzyme(s) responsible for the receptor modifications. Our knowledge about the molecular basis of the desensitization of FSH responses is rather limited. The proposed studies should help narrow this gap. Since the gonadotropins play central roles in male and female reproduction, imbalances in the circulating levels of these hormones or in the ability of their target cells to respond to then usually has catastrophic effects on reproductive processes. Thus, a complete under- standing of the regulation of gonadotropin actions is a major aspect of the field of reproductive biology.
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