Abstract

The general aims of the proposed research are to define the molecular mechanisms for the regulation of cyclic nucleotide metabolism in normal mammalian tissues. Specific emphasis will be placed on the identification, characterization, regulation and physiological roles for each member of the cGMP-stimulated and Ca++/calmodulin-dependent families of cyclic nucleotide phosphodiesterase. Four major approaches will be emphasized. First, full length cDNAs for each different isozyme will be isolated, characterized and expressed. Secondly, the domain organizations and interactions will be dissected using mutagenesis, deletion analysis, and chimeric PDE constructs. Thirdly, physiological function and regulation by phosphorylation and by hormones will be studied in both intact cells and in in vitro. Finally, two promising new techniques for isolation of cDNAs for novel cyclic nucleotide phosphodiesterases will be explored.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK021723-17
Application #
2137604
Study Section
Biochemistry Study Section (BIO)
Project Start
1978-09-15
Project End
1995-08-31
Budget Start
1994-09-30
Budget End
1995-08-31
Support Year
17
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Temkitthawon, Prapapan; Hinds, Thomas R; Beavo, Joseph A et al. (2011) Kaempferia parviflora, a plant used in traditional medicine to enhance sexual performance contains large amounts of low affinity PDE5 inhibitors. J Ethnopharmacol 137:1437-41
Percival, Justin M; Adamo, Candace M; Beavo, Joseph A et al. (2011) Evaluation of the therapeutic utility of phosphodiesterase 5A inhibition in the mdx mouse model of duchenne muscular dystrophy. Handb Exp Pharmacol :323-44
Surapisitchat, James; Beavo, Joseph A (2011) Regulation of endothelial barrier function by cyclic nucleotides: the role of phosphodiesterases. Handb Exp Pharmacol :193-210
Hertz, Angie L; Bender, Andrew T; Smith, Kimberly C et al. (2009) Elevated cyclic AMP and PDE4 inhibition induce chemokine expression in human monocyte-derived macrophages. Proc Natl Acad Sci U S A 106:21978-83
Poppe, Heiko; Rybalkin, Sergei D; Rehmann, Holger et al. (2008) Cyclic nucleotide analogs as probes of signaling pathways. Nat Methods 5:277-8
Martinez, Sergio E; Heikaus, Clemens C; Klevit, Rachel E et al. (2008) The structure of the GAF A domain from phosphodiesterase 6C reveals determinants of cGMP binding, a conserved binding surface, and a large cGMP-dependent conformational change. J Biol Chem 283:25913-9
Askari, Bardia; Kanter, Jenny E; Sherrid, Ashley M et al. (2007) Rosiglitazone inhibits acyl-CoA synthetase activity and fatty acid partitioning to diacylglycerol and triacylglycerol via a peroxisome proliferator-activated receptor-gamma-independent mechanism in human arterial smooth muscle cells and macrophages. Diabetes 56:1143-52
Surapisitchat, James; Jeon, Kye-Im; Yan, Chen et al. (2007) Differential regulation of endothelial cell permeability by cGMP via phosphodiesterases 2 and 3. Circ Res 101:811-8
Conti, Marco; Beavo, Joseph (2007) Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 76:481-511
Laxman, Sunil; Riechers, Aaron; Sadilek, Martin et al. (2006) Hydrolysis products of cAMP analogs cause transformation of Trypanosoma brucei from slender to stumpy-like forms. Proc Natl Acad Sci U S A 103:19194-9

Showing the most recent 10 out of 76 publications