title: Clinical and molecular genetics of the phosphodiesterases (PDEs).
abstract: Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that have the unique function of terminating cyclic nucleotide signaling by catalyzing the hydrolysis of cAMP and GMP. They are critical regulators of the intracellular concentrations of cAMP and cGMP as well as of their signaling pathways and downstream biological effects. PDEs have been exploited pharmacologically for more than half a century, and some of the most successful drugs worldwide today affect PDE function. Recently, mutations in PDE genes have been identified as causative of certain human genetic diseases; even more recently, functional variants of PDE genes have been suggested to play a potential role in predisposition to tumors and/or cancer, especially in cAMP-sensitive tissues. Mouse models have been developed that point to wide developmental effects of PDEs from heart function to reproduction, to tumors, and beyond. This review brings together knowledge from a variety of disciplines (biochemistry and pharmacology, oncology, endocrinology, and reproductive sciences) with emphasis on recent research on PDEs, how PDEs affect cAMP and cGMP signaling in health and disease, and what pharmacological exploitations of PDEs may be useful in modulating cyclic nucleotide signaling in a way that prevents or treats certain human diseases.
authors: Section on Endocrinology Genetics (M.F.A., F.R.F., E.B., A.H., I.L., R.B.d.A., C.A.S.), Program on Developmental Endocrinology Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland 20892; Section of Endocrinology (M.F.A.), University Hospital of Brasilia, Faculty of Medicine, University of Brasilia, Brasilia 70840-901, Brazil; Group for Advanced Molecular Investigation (F.R.F., R.B.d.A.), Graduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba 80215-901, Brazil; Cardiovascular Pulmonary Branch (F.A., V.M.), National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland 20892; and Pediatric Endocrinology Inter-Institute Training Program (C.A.S.), NICHD, NIH, Bethesda, Maryland 20892.
authors: Monalisa F
authors: MF
authors: Azevedo
authors: Fabio R
authors: FR
authors: Faucz
authors: Eirini
authors: E
authors: Bimpaki
authors: Anelia
authors: A
authors: Horvath
authors: Isaac
authors: I
authors: Levy
authors: Rodrigo B
authors: RB
authors: de Alexandre
authors: Faiyaz
authors: F
authors: Ahmad
authors: Vincent
authors: V
authors: Manganiello
authors: Constantine A
authors: CA
authors: Stratakis
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP