Regulation of GnRH receptor signaling by lipid rafts

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DESCRIPTION (provided by applicant): Gonadotropin-releasing hormone (GnRH) exerts its biological effects by binding to its cognate receptor on the surface of pituitary gonadotropes and stimulating the synthesis and secretion of luteinizing hormone and follicle-stimulating hormone. At the molecular level, engagement of the GnRH receptor initiates a complex series of signaling events including activation of the mitogen-activated protein kinase (MAPK) pathways; this activation is required for the induction of several genes essential for gonadotrope function. Understanding the regulation of GnRH-induced MAPK signaling is thus of great importance in reproductive endocrinology. One mechanism by which signaling pathways are regulated involves subcellular compartmentalization of signaling molecules through their association with specialized plasma membrane domains called lipid rafts. Lipid rafts are cholesterol and sphingolipid rich membrane domains with distinct biophysical properties that have been shown to function as platforms for the assembly of multi-protein signaling complexes. Here we provide preliminary evidence that the GnRH receptor as well as key MAPK signaling molecules are associated with lipid rafts in the murine alphaT3-1 gonadotrope cell line. This proposal outlines a set of experiments designed to test the hypothesis that lipid rafts regulate GnRH-induced MAPK signaling in gonadotropes by facilitating the compartmentalized assembly of definable MAPK signaling modules. We will use a variety of biochemical, molecular, and cell-biological techniques to study the role of lipid rafts in GnRH-induced MAPK signaling both in alphaT3-1 cells, as well as in primary differentiated mouse gonadotropes.