The overall aim of this proposal is to understand the role of the cAMP-specific phosphodiesterases (cAMP-PDEs) in hormone action. During the past funded period we have demonstrated that the cAMP- PDEs are regulated by FSH and TSH in a short term fashion via phosphorylation, and in a long term fashion via regulation of PDE gene expression. We have also demonstrated that multiple variants are derived from each of the PDE genes and that cAMP-PDEs are localized in specific subcellular structures. We now propose to continue these studies by investigating the role of these PDE variants in hormone action. The studies will be organized along three specific aims. In the first specific aim we will investigate the mechanism by which TSH causes a rapid activation of one of these PDE variants. The residues phosphorylated by TSH stimulation in the intact thyroid cell will be determined. Site directed mutagenesis will then be used to study the function of these phosphorylation sites in the enzyme activation. In the second specific aim, the role of the different PDE variants originating from the PDE4D gene will be investigated. A heterologous hormone responsive system expressing different cAMP- PDE variants will be used to study their impact on steroidogenesis and gene expression. After showing that cAMP-PDEs are targeted to different cellular compartments, the mechanism mediating this targeting will be investigated. In the third specific aim, the hypothesis that anchoring proteins target a PDE to different subcellular compartments will be tested by investigating the function of novel putative PDE-binding proteins that we have identified. These studies will further our understanding of the mechanism of TSH and FSH action in the endocrine target cell. They will also help define new targets for pharmacological intervention in endocrine disorders.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD020788-12
Application #
2673517
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Margolis, Ronald N
Project Start
1985-02-01
Project End
2002-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
12
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Stanford University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Hsieh, Minnie; Zamah, A Musa; Conti, Marco (2009) Epidermal growth factor-like growth factors in the follicular fluid: role in oocyte development and maturation. Semin Reprod Med 27:52-61
Bruss, Matthew D; Richter, Wito; Horner, Kathleen et al. (2008) Critical role of PDE4D in beta2-adrenoceptor-dependent cAMP signaling in mouse embryonic fibroblasts. J Biol Chem 283:22430-42
Richter, Wito; Day, Peter; Agrawal, Rani et al. (2008) Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4. EMBO J 27:384-93
Leroy, Jerome; Abi-Gerges, Aniella; Nikolaev, Viacheslav O et al. (2008) Spatiotemporal dynamics of beta-adrenergic cAMP signals and L-type Ca2+ channel regulation in adult rat ventricular myocytes: role of phosphodiesterases. Circ Res 102:1091-100
Zhang, Han-Ting; Huang, Ying; Masood, Anbrin et al. (2008) Anxiogenic-like behavioral phenotype of mice deficient in phosphodiesterase 4B (PDE4B). Neuropsychopharmacology 33:1611-23
Lee, Ji Hyun; Richter, Wito; Namkung, Wan et al. (2007) Dynamic regulation of cystic fibrosis transmembrane conductance regulator by competitive interactions of molecular adaptors. J Biol Chem 282:10414-22
Conti, Marco; Beavo, Joseph (2007) Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 76:481-511
Rich, Thomas C; Xin, Wenkuan; Mehats, Celine et al. (2007) Cellular mechanisms underlying prostaglandin-induced transient cAMP signals near the plasma membrane of HEK-293 cells. Am J Physiol Cell Physiol 292:C319-31
Conti, Marco; Hsieh, Minnie; Park, Jy-Young et al. (2006) Role of the epidermal growth factor network in ovarian follicles. Mol Endocrinol 20:715-23
Rochais, Francesca; Abi-Gerges, Aniella; Horner, Kathleen et al. (2006) A specific pattern of phosphodiesterases controls the cAMP signals generated by different Gs-coupled receptors in adult rat ventricular myocytes. Circ Res 98:1081-8

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