One of the principal loci involved in the regulation of the actions of lutropin/choriogonadotropin (LH/CG) is the LH/CG receptor (LH/CG-R). The regulation that occurs at this level can be due to an attenuation of the ability of a constant number of receptors to activate the effector system (uncoupling) or to a decrease in the actual number of receptors (down-regulation). Uncoupling and/or down-regulation of the LH/CG-R can be elicited not only by LH/CG, but also by other hormones that do not bind to the LH/CG-R (such as epidermal growth factor) and by some second messengers such as phorbol esters and cAMP analogues. Although it may appear as if down-regulation and uncoupling are redundant (given that they are elicited by the same stimuli), their different time courses suggest that their relative importance in the overall refractoriness of the cell may vary in a temporal fashion. The studies proposed herein seek to understand the molecular basis of the regulation of the actions of LH/CG that occur at the level of the LH/CG-R. Using clonal strains of cultured Leydig tumor cells that express functional LH/CG-Rs, and novel clonal cell lines obtained by permanent transfection with the wild type or mutated forms of the LH/CG-R cDNA we propose to (1) identify post-translational modifications of the LH/CG-R that are responsible for uncoupling the receptor from Gs; (2) determine if the rapid rate of endocytosis of LH/CG requires the interaction of the LH/CG-R with Gs; and (3) characterize the transcriptional regulation of the LH/CG-R gene in MA- 10 Leydig tumor cells. A complete understanding of the regulation of hormone action is a major aspect of the field of endocrinology. Since the LH/CG-R is a member of the growing family of G-protein coupled receptors, our data will provide important information not only about the regulation of the actions of LH/CG, but also about the mechanisms involved in the regulation of the numbers and functional activity of this important family of receptors.
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