Clinical and Molecular Genetics of the Phosphodiesterases (PDEs)

R E V I E W Clinical and Molecular Genetics of the Phosphodiesterases (PDEs) Monalisa F. Azevedo, Fabio R. Faucz, Eirini Bimpaki, Anelia Horvath, Isaac Levy, Rodrigo B. de Alexandre, Faiyaz Ahmad, Vincent Manganiello, and Constantine A. Stratakis 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 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,mutationsinPDEgeneshavebeenidentifiedascausativeofcertainhumangeneticdiseases;evenmore 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. (Endocrine Reviews 35: 195–233, 2014) I. Introduction II. The Phosphodiesterase (PDE) Superfamily A. General structure B. cAMP and cGMP signaling pathways C. Compartmentalization of cyclic nucleotide signaling pathways III. PDE Families A. PDE1 B. PDE2 C. PDE3 D. PDE4 E. PDE5 F. PDE6 G. PDE7 H. PDE8 I. PDE9 J. PDE10 K. PDE11 IV. PDE Inhibitors A. Overview ISSN Print 0163-769X ISSN Online 1945-7189 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received May 15, 2013. Accepted November 6, 2013. First Published Online December 5, 2013 doi: 10.1210/er.2013-1053 B. PDE5 inhibitors and their clinical use in erectile dysfunction, pulmonary hypertension, and other disorders C. PDE4 inhibitors and their promising clinical uses D. PDE inhibitors and the cardiovascular system E. PDE inhibitors and cancer V. Conclusions and Perspectives I. Introduction AMP and cGMP are intracellular second messengers that play a central role in signal transduction cascades that regulate many critical physiological and pathophys- c Abbreviations: AhR, aryl hydrocarbon receptor; AKAP, A-kinase-anchoring protein; ␤-AR, ␤-adrenergic receptor; CaM, calmodulin; COPD, chronic obstructive pulmonary disease; CNGC, cyclic nucleotide-gated channel; CREB, cAMP response element-binding protein; EPAC, exchange protein activated by cAMP; FRET, fluorescence resonance energy transfer; GAF, cGMP-specific PDEs, adenylyl cyclases and FhIA; GPCR, G protein-coupled receptor; IBMX, 1-methyl-3-isobutylxanthine; LTCC, L-type Ca2⫹ channel; mAKAP, muscle-specific AKAP; MDD, major depressive disorder; MPF, maturation-promoting factor; NO, nitric oxide; NOS, NO synthase; PAS, per-arnt-sim; PCOS, polycystic ovary syndrome; PDE, phosphodiesterase; PI3K, phosphatidylinositol-3 kinase; PKA, protein kinase A; PKB, protein kinase B; PKG, cGMP-dependent protein kinase; PLB, phospholamban; PP, protein phosphatase; REC, cheY-homologous receiver domain; RyR, ryanodine receptor; SERCA2, SR Ca2⫹ ATPase; sGC, soluble guanylyl cyclase; SR, sarcoplasmic reticulum; UCR, upstream conserved region. Endocrine Reviews, April 2014, 35(2):195–233 edrv.endojournals.org 195 196 Azevedo et al Genetics of Phosphodiesterases Figure 1. Endocrine Reviews, April 2014, 35(2):195–233 tumor development. As seen in Figure 1, adenylyl and guanylyl cyclases catalyze formation of cAMP and cGMP from ATP and GTP, respectively. Signal transduction is initiated by cAMP- and cGMP-induced activation of cAMP- and cGMPdependent protein kinases (PKA and PKG, respectively), with subsequent phosphorylation of key proteins and activation of downstream pathways. In addition, cyclic nucleotide binding proteins serve as direct signal transducers, ie, cAMP-activated guanine nucleotide exchange proteins (EPACs) that regulate Rap GTPases (guanine nucleotide triphosphatases), cAMP- and cGMP-gated ion channels, and several cyclic nucleotide phosphodiesterases (PDEs), especially PDE2, -5, and -6, which contain allosteric, noncatalytic, cyclic nucleotide-binding domains (Figure 1). II. The Phosphodiesterase (PDE) Superfamily PDEs, which were identified almost immediately after the discovery of Figure 1. Cyclic nucleotide signaling and regulation. AC, adenylyl cyclase; ANP, atrial natriuretic cAMP (1–3), represent a large family peptide; BNP, B-type natriuretic peptide; B-Raf, B-Raf protein kinase; CNG-channel, cyclic of ubiquitously expressed hydronucleotide-gated channel; CNP, C-type natriuretic peptide; pGC, particulate guanylyl cyclase; lases that control the intracellular PKG, cGMP-dependent protein kinase; Rap, Ras-related protein; sAC soluble AC; sGC, soluble guanylyl cyclase. levels of cyclic nucleotides by hydrolyzing cAMP and cGMP to 5⬘AMP iological processes, including cellular growth, differentiand 5⬘GMP, respectively. Because they catalyze the sole 2⫹ ation, and proliferation; Ca -dependent signaling; reknown enzymatic reaction for terminating cyclic nucleoproduction; cardiac function; vision; inflammation; and tide signals, PDEs are critical regulators of the myriad physiological and Figure 2. pathophysiological processes under cyclic nucleotide control in health and disease. PDEs constitute a large and complex superfamily that contains 11 PDE gene families (PDE1 to PDE11), comprising 21 genes that generate approximately 100 (or more) proteins via alternative splicing of mRNA or multiple promoters and transcription start sites (Figures 2 and 3) (4, 5). PDE families are structurally related and highly reguFigure 2. General structure of PDE enzyme molecules. HD, hydrophobic domains. doi: 10 (...truncated)