The human pituitary, hormones lutropin (LH), follitropin (FSH) and thyrotropin constitute a family of glycoprotein heterodimers comprised of a common alpha-subunit and a hormone-specific beta-subunit. It is the unique beta subunit that determines the biological specificity of each hormone. A critical feature of these proteins is their unique secretory patterns. LH is released through a regulated pathway, i.e, they are released by secretagogues, whereas FSH is primarily secreted constitutively. The asparagine-linked (N) otigosaccharides on these glycoproteins are hormone specific: The terminal carbohydrate on LH is sulfate, whereas for FSH it is sialic acid. The primary objective of this proposal is to address the rote of the carbohydrate structure to the routing and sorting of LH and FSH, specifically the relationship of terminal sulfate/sialic acid to this process. The question addressed here is whether terminal N-linked sulfate is a signal for sorting to the regulated pathway and constitutive release of FSH is linked to sialylation. FSHbeta-LHbeta chimeras and point mutants will be constructed to identify sequences that govern their unique sorting patterns. The established GH3 cell ling will be used to screen the structural features in FSH/LH that govern regulated vs. constitutive secretion. This cell line, which is derived from rat pituitary somatotropes, contains storage vesicles and is responsive to secretagogues. Informative human LH and FSH variants identified in the GH3 line will be expressed in pituitaries from transgenic mice lacking the endogenous LHbeta and FSHbeta genes in an attempt to verify the tissue culture data. These experiments will be critical in attempting to define the structural motifs involved with intracellular trafficking, and specifically the sorting and packaging signals for the glycoprotein hormone family. The ability to reroute the pituitary gonadotropins m vivo could also represent an important model for gonadal dysfunction and potentially provide a novel way to examine normal and ultimately pathophysiological events in the human reproductive tract.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Reproductive Endocrinology Study Section (REN)
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Malozowski, Saul N
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Washington University
Other Basic Sciences
Schools of Medicine
Saint Louis
United States
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Pearl, Christopher A; Boime, Irving (2009) Sulfation of LH does not affect intracellular trafficking. Mol Cell Endocrinol 309:76-81
Jablonka-Shariff, Albina; Kumar, T Rajendra; Eklund, Joshua et al. (2006) Single-chain, triple-domain gonadotropin analogs with disulfide bond mutations in the alpha-subunit elicit dual follitropin and lutropin activities in vivo. Mol Endocrinol 20:1437-46