Studies dealing with the biochemical and molecular mechanism of gonadotropin releasing hormone (GnRH) action have served to (a) identify new human and veterinary uses for GnRH and its analogs, (b) bring these uses to fruition through a rational process based on understanding of the mechanism of hormone action, and (c) provide the means for anticipating, understanding, and ameliorating side-effects of the agents. FDA approvals of GnRH agonists for the treatment of prostate cancer, endometriosis, and precocious puberty, as well as for the use of natural sequence GnRH to induce ovulation and to test the hypothalamic-pituitary-gonadal axis, are examples of the clinical usefulness derived from these fundamental observations. There are multiple advantages to the study of GnRH-stimulation of the gonadotrope that make it facile to collect interpretable data (a) GnRH stimulation of the gonadotrope cell has clearly defined, specific and measurable endpoints release of endocr ine (a nd potentially endocrine) substances (LH, FSH, secretogranin II, ?-subunit of gonadotropin), regulation of target cell sensitivity, regulation of the GnRH receptor, and biosynthesis of released substances. (b) The releasing hormone itself (as well as its agonists and antagonists) can be radioiodinated to high specific activity. (c) Many (>3,000) analogs exist that can be chemically derivatized without loss of biological activity. Antagonists and agonists which bind the receptor with greater affinities than the natural sequence GnRH are available. (d) Virtually all known agonists and antagonists are Apure@ in action and metabolically stable agonists are available. The present project is divided into areas of focus that form the basis of organization of the work. The first will provide information on the structure of the GnRH receptor and early actions following the interaction of the receptor with GnRH and its analogs and should advance our understanding of the receptor in the mec hanism of GnRH action. The second area will provide information on the relationship between the multiple effector mechanisms already implicated in GnRH action with the multiple actions stimulated by the releasing hormone (release of multiple endocrine substances, regulation of target cell responsiveness, biosynthesis, and regulation of receptor number). This is important since considerable confusion remains regarding these relations. The third area involves understanding the molecular sites of action of activin and inhibin in relation to GnRH action and are significant to understand the actions of these agents in vivo. The approaches will take advantage of newly available genetic probes, antisera, and cell lines. FUNDING NIH HD19899 PUBLICATIONS Conn PM, Parker JV. Animal rights reaching the public. Science 282:1417, 1998. Conn PM (editor-in-chief). Clinical Management of Diabetic Neuropathy. Contemporary Endocrinology Vol 7 (A Veves, ed). Totowa, NJ Humana, 347 pp, 1998. Conn PM (editor-in-chief). G Proteins, Receptors, and Disease. Contemporary Endocrinology Vol 6 (A Spiegel, ed). Totowa, NJ Humana, 324 pp, 1998. Conn PM, Jennes J, Janovick JA. GnRH (Gonadotropin-Releasing Hormone). In Encyclopedia of Reproduction (E Knobil, JD Neill, eds). New York, NY Academic Press, pp 464-477, 1998. Conn PM. Make science relevant, human and clear. The Scientist 12:9, 1998. Cornea A, Janovick JA, Stanislaus D, Conn PM. Redistribution of Gq/11? in pituitary gonadotrope in response to a GnRH agonist. Endocrinology 1:397-402, 1998. Lin X, Janovick JA, Brothers S, Blomenrvhr J, Bogerd J, Conn PM. Addition of catfish gonadotropin-releasing hormone (GnRH) receptor intracellular carboxyl-terminal tail to rat GnRH receptor alters receptor expression and regulation. Mol Endocrinol 12:161-171, 1998. Lin X, Janovick JA, Conn PM. Mutations at the consensus phosphorylation sites in the third intracellular loop of the rat GnRH receptor effects on receptor ligand binding and signal transduction. Biol Reprod 59:1470-1476, 1998. Lin X, Conn PM. Transcriptional activation of gonadotropin-releasing hormone (GnRH) receptor gene by GnRH and cyclic AMP. Endocrinology 139:3896-3902, 1998. Lin X, Cornea A, Janovick JA, Conn PM. Visualization of unoccupied and occupied gonadotropin-releasing hormone receptor in living cells. Mol Cell Endocrinol 146:27-37, 1998. Stanislaus D, Ponder S, Ji T, Conn PM. GnRH receptor couples to multiple G-proteins in gonadotropes and in GGH3 cells evidence from palmitoylation and overexpression of G-proteins. Biol Reprod 59:579-586, 1998. Stanislaus D, Janovick JA, Ji T, Wilkie T, Offermanns S, Conn PM. Gonadotropin and gonadal steroid release in response to a GnRH agonist in Gq? and G11? knockout mice. Endocrinology 139:2710-2717, 1998. Stanislaus D, Pinter J, Janovick JA, Conn PM. Mechanisms mediating multiple physiological responses to gonadotropin-releasing hormone. Mol Cell Endocrinol 144:1-10, 1998. Ulloa-Aguirre A, Stanislaus D, Arora V, Vddndnen J, Brothers S, Janovick JA, Conn PM. The third intracellular loop of the rat gonadotropin-releasing hormone (GnRH) receptor couples the receptor to Gs- and Gq/11-mediated signal transduction pathways evidence from loop fragment transfection in GGH3 cells. Endocrinology 5:2472-2478, 1998.
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