Abstract

The objective of this proposal is to elucidate the signaling pathways in GnRH neurons which constitute the clock for pulsatile GnRH release and that mediate the action of neurotransmitters. The investigator proposes to determine the relationship between intracellular and extracellular cAMP levels and GnRH secretion; to determine whether GT1 cells express cAMP gated cation channels and how they are regulated; to determine which isoforms of adenyl cyclase and phosphodiesterase are expressed in GT1 cells and how they are regulated, particularly isoforms that are regulated by PKA; and, to determine cAMP and GnRH secretion dynamics in GT1 cells stably expressing either the constitutively-active PDE-4D isoform or a dominant-negative PKA regulatory subunit. Finally, if effects are observed in the biochemical studies, the effector molecules will be targeted to GnRH neurons using transgenic approaches in order to determine their physiological significance.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD008924-23
Application #
6125597
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
De Paolo, Louis V
Project Start
1978-04-01
Project End
2001-11-30
Budget Start
1999-12-01
Budget End
2001-11-30
Support Year
23
Fiscal Year
2000
Total Cost
$249,024
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Tsai, Pei-San; Moenter, Suzanne M; Postigo, Hector R et al. (2005) Targeted expression of a dominant-negative fibroblast growth factor (FGF) receptor in gonadotropin-releasing hormone (GnRH) neurons reduces FGF responsiveness and the size of GnRH neuronal population. Mol Endocrinol 19:225-36
Yoshida, Hiroshi; Beltran-Parrazal, Luis; Butler, Paul et al. (2003) Lowering cyclic adenosine-3',5'-monophosphate (cAMP) levels by expression of a cAMP-specific phosphodiesterase decreases intrinsic pulsatile gonadotropin-releasing hormone secretion from GT1 cells. Mol Endocrinol 17:1982-90
Paruthiyil, Sreenivasan; eL Majdoubi, Mohammed; Conti, Marco et al. (2002) Phosphodiesterase expression targeted to gonadotropin-releasing hormone neurons inhibits luteinizing hormone pulses in transgenic rats. Proc Natl Acad Sci U S A 99:17191-6
Weiner, R I; Charles, A (2001) Regulation of gonadotropin-releasing hormone release by cyclic AMP signalling pathways. Growth Horm IGF Res 11 Suppl A:S9-15
Vitalis, E A; Costantin, J L; Tsai, P S et al. (2000) Role of the cAMP signaling pathway in the regulation of gonadotropin-releasing hormone secretion in GT1 cells. Proc Natl Acad Sci U S A 97:1861-6
Sakakibara, H; Conti, M; Weiner, R I (1998) Role of phosphodiesterases in the regulation of gonadotropin- releasing hormone secretion in GT1 cells. Neuroendocrinology 68:365-73
Tsai, P S; Werner, S; Weiner, R I (1995) Basic fibroblast growth factor is a neurotropic factor in GT1 gonadotropin-releasing hormone neuronal cell lines. Endocrinology 136:3831-8
Martinez de la Escalera, G; Choi, A L; Weiner, R I (1995) Signaling pathways involved in GnRH secretion in GT1 cells. Neuroendocrinology 61:310-7
Mellon, S H; Miller, W L; Bair, S R et al. (1994) Steroidogenic adrenocortical cell lines produced by genetically targeted tumorigenesis in transgenic mice. Mol Endocrinol 8:97-108
Milenkovic, L; D'Angelo, G; Kelly, P A et al. (1994) Inhibition of gonadotropin hormone-releasing hormone release by prolactin from GT1 neuronal cell lines through prolactin receptors. Proc Natl Acad Sci U S A 91:1244-7

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