Abstract
Cyclic nucleotide phosphodiesterases (PDEs) are promising targets for pharmacological intervention. The presence of multiple PDE genes, diversity of the isoforms produced from each gene, selective tissue and cellular expression of the isoforms, compartmentation within cells, and an array of conformations of PDE proteins are some of the properties that challenge the development of drugs that target these enzymes. Nevertheless, many of the characteristics of PDEs are also viewed as unique opportunities to increase specificity and selectivity when designing novel compounds for certain therapeutic indications. This chapter provides a summary of the major concepts related to the design and use of PDE inhibitors. The overall structure and properties of the catalytic domain and conformations of PDEs are summarized in light of the most recent X-ray crystal structures. The distinctive properties of catalytic domains of different families as well as the technical challenges associated with probing PDE properties and their interactions with small molecules are discussed. The effect of posttranslational modifications and protein–protein interactions are additional factors to be considered when designing PDE inhibitors. PDE inhibitor interaction with other proteins needs to be taken into account and is also discussed.
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References
Abdulkadir Coban T, Beydemir S, Gucin I, Ekinci D, Innocenti A, Vullo D, Supuran CT (2009) Sildenafil is a strong activator of mammalian carbonic anhydrase isoforms I-XIV. Bioorg Med Chem 17:5791–5795
Alvarez R, Sette C, Yang D, Eglen R, Wilhelm R, Shelton ER, Conti M (1995) Activation and selective inhibition of a cyclic AMP-specific phosphodiesterase, PDE4D3. Mol Pharmacol 48:616–622
Aravind L, Ponting CP (1997) The GAF domain: an evolutionary link between diverse phototransducing proteins. Trends Biochem Sci 22:458–459
Baillie GS, Huston E, Scotland G, Hodgkin M, Gall I, Peden AH, MacKenzie C, Houslay ES, Currie R, Pettitt R, Walmsley AR, Wakelam MJO, Warwicker J, Houslay MD (2002) TAPAS-1, a novel microdomain within the unique N-terminal region of the PDE4A1 cAMP specific phosphodiesterase that allows rapid, Ca2+-triggered membrane association with selectivity for interaction with phosphatidic acid. J Biol Chem 277:28298–28309
Baillie GS, Sood A, McPhee I, Gall I, Perry SJ, Lefkowitz RJ, Houslay MD (2003) β-arrestin mediated PDE4 cAMP phosphodiesterase recruitment regulates β2-adrenoceptor switching from Gs to Gi. Proc Natl Acad Sci 100:940–945
Barnes P (2006) Theophylline for COPD. Thorax 61:742–744
Barnes AP, Livera G, Huang P, Sun C, O’Neal WK, Conti M, Stutts MJ, Milgram SL (2005) Phosphodiesterase 4D forms a cAMP diffusion barrier at the apical membrane of the airway epithelium. J Biol Chem 280:7997–8003
Barren B, Gakhar L, Muradov H, Boyd KK, Ramaswamy S, Artemyev NO (2009) Structural basis of phosphodiesterase 6 inhibition by the C-terminal region of the gamma-subunit. EMBO J 28:3613–3622
Bazhin AV, Tambor V, Dikov B, Philippov PP, Schadendorf D, Eichmuller SB (2010) cGMP-phosphodiesterase 6, transducin and Wnt5a/Frizzled-2-signaling control cGMP and Ca(2+) homeostasis in melanoma cells. Cell Mol Life Sci 67:817–828
Beavo JA, Brunton LL (2002) Cyclic nucleotide research - still expanding after half a century. Nat Rev Mol Cell Biol 3:710–718
Beltman J, Becker DE, Butt E, Jensen GS, Rybalkin SD, Jastorff B, Beavo JA (1995) Characterization of cyclic nucleotide phosphodiesterases with cyclic GMP analogs: topology of the catalytic domains. Mol Pharmacol 47:330–339
Bender AT, Beavo J (2006) Cyclic nucleotide phosphodiesterases: molecualr regulation to clinical use. Pharmacol Rev 58:488–520
Bessay E, Blount M, Zoraghi R, Beasley A, Grimes K, Francis S, Corbin JD (2008) Phosphorylation increases affinity of the phosphodiesterase-5 catalytic site for tadalafil. J Pharmacol Exp Ther 325:62–68
Blount MA, Beasley A, Zoraghi R, Sekhar KR, Bessay EP, Francis SH, Corbin JD (2004) Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation. Mol Pharmacol 66:144–152
Blount MA, Zoraghi R, Ke H, Bessay EP, Corbin JD, Francis SH (2006) A 46-amino acid segment in phosphodiesterase-5 GAF-B domain provides for high vardenafil potency over sildenafil and tadalafil and is involved in phosphodiesterase-5 dimerization. Mol Pharmacol 70:1822–1831
Blount MA, Zoraghi R, Bessay EP, Beasley A, Francis SH, Corbin JD (2007) Conversion of phosphodiesterase-5 (PDE5) catalytic site to higher affinity by PDE5 inhibitors. J Pharmacol Exp Ther 323:730–737
Bolger G, Michaeli T, Martins T, St John T, Steiner B, Rodgers L, Riggs M, Wigler M, Ferguson K (1993) A family of human phosphodiesterases homologous to the dunce learning and memory gene product of Drosophila melanogaster are potential targets for antidepressant drugs. Mol Cell Biol 13:6558–6571
Bolger GB, Peden AH, Steele MR, MacKenzie C, McEwan DG, Wallace DA, Huston E, Baillie GS, Houslay MD (2003) Attenuation of the activity of the cAMP-specific phosphodiesterase PDE4A5 by interaction with the immunophilin XAP2. J Biol Chem 278:33351–33363
Bolger GB, Conti M, Houslay MD (2006) Cellular functions of phosphodiesterase-4 enzymes. In: Beavo J, Francis S, Houslay MD (eds) Phosphodiesterases in health and disease. CRC, Boca Raton, pp 99–130, Ch. 6
Bos JL (2006) Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci 31:680–686
Braumann T, Erneux C, Petridis G, Stohrer WD, Jastorff B (1986) Hydrolysis of cyclic nucleotides by a purified cGMP-stimulated phosphodiesterase: structural requirements for hydrolysis. Biochim Biophys Acta 871:199–206
Burgers PM, Eckstein F (1979) Stereochemistry of internucleotide bond formation by polynucleotide phosphorylase from Micrococcus luteus. Biochemistry 18:450–454
Burgin AB, Magnusson OT, Singh J, Witte P, Staker BL, Bjornsson JM, Thorsteinsdottir M, Hrafnsdottir S, Hagen T, Kiselyov AS, Stewart LJ, Gurney ME (2010) Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol 28:63–70
Butcher RW, Sutherland EW (1962) Adenosine 3′, 5′-phosphate in biological materials. I. Purification and properties of cyclic 3′, 5′-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3′, 5′-phosphate in human urine. J Biol Chem 237:1244–1250
Butt E, Beltman J, Becker DE, Jensen GS, Rybalkin SD, Jastorff B, Beavo JA (1995) Characterization of cyclic nucleotide phosphodiesterases with cyclic AMP analogs: topology of the catalytic sites and comparison with other cyclic AMP-binding proteins. Mol Pharmacol 47:340–347
Castro LR, Verde I, Cooper DM, Fischmeister R (2006) Cyclic guanosine monophosphate compartmentation in rat cardiac myocytes. Circulation 113:2221–2228
Charbonneau H (1990) Structure-function relationships among cyclic nucleotide phosphodiesterases. In: Beavo J, Houslay MD (eds) Cyclic nucleotide phosphodiesterases: structure, regulation and drug action. Wiley, New York, pp 267–296
Chen G, Wang H, Robinson H, Cai J, Wan Y, Ke H (2008) An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies. Biochem Pharmacol 75:1717–1728
Cheung PP, Yu L, Zhang H, Colman RW (1998) Partial characterization of the active site human platelet cAMP phosphodiesterase, PDE3A, by site-directed mutagenesis. Arch Biochem Biophys 360:99–104
Collins DM, Murdoch H, Dunlop AJ, Charych E, Baillie GS, Herberg FW, Brandon N, Prinz A, Houslay MD (2008) Ndel1 alters its conformation by sequestering cAMP-specific phosphodiesterase-4D3 (PDE4D3) in a manner that is dynamically regulated through Protein Kinase A (PKA). Cell Signal 20:2356–2369
Conti M, Beavo J (2007) Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 76:481–511
Conti M, Richter W, Mehats C, Livera G, Park JY, Jin C (2003) Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J Biol Chem 278:5493–5496
Corbin JD, Francis SH (1999) Cyclic GMP phosphodiesterase-5: target of sildenafil. J Biol Chem 274:13729–13732
Corbin JD, Sugden PH, Lincoln TM, Keely SL (1977) Compartmentalization of adenosine 3′:5′-monophosphate and adenosine 3′:5′-monophosphate-dependent protein kinase in heart tissue. J Biol Chem 252:3854–3861
Corbin JD, Turko IV, Beasley A, Francis SH (2000) Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Eur J Biochem 267:2760–2767
Corbin JD, Blount MA, Weeks JL 2nd, Beasley A, Kuhn KP, Ho YS, Saidi LF, Hurley JH, Kotera J, Francis SH (2003) [3H]sildenafil binding to phosphodiesterase-5 is specific, kinetically heterogeneous, and stimulated by cGMP. Mol Pharmacol 63:1364–1372
Cortijo J, Bou J, Beleta J, Cardelus I, Llenas J, Morcillo E, Gristwood RW (1993) Investigation into the role of phosphodiesterase IV in bronchorelaxation, including studies with human bronchus. Br J Pharmacol 108:562–568
Cote RH (2006) Photoreceptor phosphodiesterase (PDE6): a G-protein-activated PDE regulating visual excitation in rod and cone photoreceptor cells. In: Beavo J, Francis SH, Houslay MD (eds) Cyclic nucleotide phosphodiesterases in health and disease. CRC Press, Boca Raton, pp 165–193
Dent G, Rabe K (1996) Effects of theophylline and non-selective xanthine derivatives on PDE isoenzymes and cellular function. In: Schudt C, Dent G, Rabe KF (eds) Handbook of immunopharmacology: phosphodiesterase inhibitors. Academic, San Diego, pp 41–64
Erneux C, Miot F, Boeynaems JM, Dumont JE (1982) Paradoxical stimulation by 1-methyl-3-isobutylxanthine of rat liver cyclic AMP phosphodiesterase activity. FEBS Lett 142:251–254
Fink TL, Francis SH, Beasley A, Grimes KA, Corbin JD (1999) Expression of an active, monomeric catalytic domain of the cGMP-binding cGMP-specific phosphodiesterase (PDE5). J Biol Chem 274:34613–34620
Francis SH, Corbin JD (1999) Cyclic nucleotide-dependent protein kinases: intracellular receptors for cAMP and cGMP action. Crit Rev Clin Lab Sci 36:275–328
Francis SH, Corbin JD (2005) Phosphodiesterase-5 inhibition: the molecular biology of erectile function and dysfunction. Urol Clin North Am 32:419–429, vi
Francis SH, Corbin JD (2009) Phosphodiesterase-5. In: Bradshaw RA, Dennis EA (eds) Handbook of cell signaling, vol 2, 2nd edn. Academic, Oxford, pp 1439–1444
Francis SH, Colbran JL, McAllister-Lucas LM, Corbin JD (1994) Zinc interactions and conserved motifs of the cGMP-binding cGMP-specific phosphodiesterase suggest that it is a zinc hydrolase. J Biol Chem 269:22477–22480
Francis SH, Zoraghi R, Kotera J, Ke H, Bessay EP, Blount MA, Corbin JD (2006) Phosphodiesterase-5: molecular characteristics relating to structure, function, and regulation. In: Beavo SHF JA, Houslay MD (eds) Cyclic nucleotide phosphodiesterases in health and disease. CRC Press, Boca Raton, pp 131–164
Francis SH, Morris GZ, Corbin JD (2008) Molecular mechanisms that could contribute to prolonged effectiveness of PDE5 inhibitors to improve erectile function. Int J Impot Res 20:333–342
Friebe A, Mullershausen F, Smolenski A, Walter U, Schultz G, Koesling D (1998) YC-1 potentiates nitric oxide- and carbon monoxide-induced cyclic GMP effects in human platelets. Mol Pharmacol 54:962–967
Galle J, Zabel U, Hubner U, Hatzelmann A, Wagner B, Wanner C, Schmidt HH (1999) Effects of the soluble guanylyl cyclase activator, YC-1, on vascular tone, cyclic GMP levels and phosphodiesterase activity. Br J Pharmacol 127:195–203
Giembycz MA (2006) Reinventing the wheel: nonselective phosphodiesterase inhibitors for chronic inflammatory diseases. In: Beavo JA, Francis SH, Houslay MD (eds) Cyclic nucleotide phosphodiesterases in health and disease. CRC Press, Boca Raton, pp 649–665
Gopal VK, Francis SH, Corbin JD (2001) Allosteric sites of phosphodiesterase-5 (PDE5). A potential role in negative feedback regulation of cGMP signaling in corpus cavernosum. Eur J Biochem 268:3304–3312
Goraya TA, Cooper DM (2005) Ca2+-calmodulin-dependent phosphodiesterase (PDE1): current perspectives. Cell Signal 17:789–797
Gross-Langenhoff M, Hofbauer K, Weber J, Schultz A, Schultz JE (2006) cAMP is a ligand for the tandem GAF domain of human phosphodiesterase 10 and cGMP for the tandem GAF domain of phosphodiesterase 11. J Biol Chem 281:2841–2846
Gurney ME, Burgin AB, Magnusson OT, Stewart LJ (2011) Small molecule allosteric modulators of phosphodiesterase 4. Francis SH, Conti M, HouslayMD (eds) Phosphodiesterases as drug targets. Springer, Heidelberg
Han P, Sonati P, Rubin C, Michaeli T (2006) PDE7A1, a cAMP-specific phosphodiesterase, inhibits cAMP-dependent protein kinase by a direct interaction with C. J Biol Chem 281:15050–15057
Handa N, Mizohata E, Kishishita S, Toyama M, Morita S, Uchikubo-Kamo T, Akasaka R, Omori K, Kotera J, Terada T, Shirouzu M, Yokoyama S (2008) Crystal structure of the GAF-B domain from human phosphodiesterase 10A complexed with its ligand, cAMP. J Biol Chem 283:19657–19664
Hayes JS, Brunton LL, Brown JH, Reese JB, Mayer SE (1979) Hormonally specific expression of cardiac protein kinase activity. Proc Natl Acad Sci USA 76:1570–1574
He F, Seryshev AB, Cowan CW, Wensel TG (2000) Multiple zinc binding sites in retinal rod cGMP phosphodiesterase, PDE6alpha beta. J Biol Chem 275:20572–20577
Heikaus CC, Stout JR, Sekharan MR, Eakin CM, Rajagopal P, Brzovic PS, Beavo JA, Klevit RE (2008) Solution structure of the cGMP binding GAF domain from phosphodiesterase 5: insights into nucleotide specificity, dimerization, and cGMP-dependent conformational change. J Biol Chem 283:22749–22759
Hirano T, Yamagata T, Gohda M, Yamagata Y, Ichikawa T, Yanagisawa S, Ueshima K, Akamatsu K, Nakanishi M, Matsunaga K, Minakata Y, Ichinose M (2006) Inhibition of reactive nitrogen specids production in COPD airways: comparison between inhaled corticosteroid and oral theophylline. Thorax 61:761–766
Hoffmann R, Wilkinson IR, McCallum JF, Engels P, Houslay MD (1998) cAMP-specific phosphodiesterase HSPDE4D3 mutants which mimic activation and changes in rolipram inhibition triggered by protein kinase A phosphorylation of Ser-54: generation of a molecular model. Biochem J 333:139–149
Houslay MD (2001) Intracellular targeting and regulation of PDE4 cAMP specific Phosphodiesterases. Prog Nucleic Acid Res Mol Biol 69:249–315
Houslay MD (2010) Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci 35:91–100
Houslay MD, Adams DR (2003) PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 370:1–18
Houslay MD, Adams DR (2010) Lockdown on phosphodiesterase-4. Nat Biotechnol 28:38–40
Houslay MD, Schafer P, Zhang K (2005) Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today 10:1503–1519
Houslay MD, Baillie GS, Maurice DH (2007) cAMP-specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalized cAMP signaling. Circ Res 100:950–966
Huai Q, Wang H, Sun Y, Kim HY, Liu Y, Ke H (2003) Three-dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity. Structure 11:865–873
Huai Q, Wang H, Zhang W, Colman RW, Robinson H, Ke H (2004) Crystal structure of phosphodiesterase 9 shows orientation variation of inhibitor 3-isobutyl-1-methylxanthine binding. Proc Natl Acad Sci USA 101(26):9624–9629
Huang D, Hinds TR, Martinez SE, Doneanu C, Beavo JA (2004) Molecular determinants of cGMP binding to chicken cone photoreceptor phosphodiesterase. J Biol Chem 279:48143–48151
Huston E, Pooley L, Julien P, Scotland G, McPhee I, Sullivan M, Bolger G, Houslay MD (1996) The human cyclic AMP-specific phosphodiesterase PDE-46 (HSPDE4A4B) expressed in transfected COS7 cells occurs as both particulate and cytosolic species that exhibit distinct kinetics of inhibition by the antidepressant rolipram. J Biol Chem 271:31334–31344
Huston E, Houslay TM, Baillie GS, Houslay MD (2006) cAMP phosphodiesterase-4A1 (PDE4A1) has provided the paradigm for the intracellular targeting of phosphodiesterases, a process that underpins compartmentalized cAMP signalling. Biochem Soc Trans 34:504–509
Huston E, Lynch M, Mohamed A, Collins DM, Hill EV, MacLeod R, Krause E, Baillie GS, Houslay MD (2008) EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation. Proc Natl Acad Sci USA 105:12791–12796
Jacobitz S, McLaughlin MM, Livi GP, Burman M, Torphy TJ (1996) Mapping the functional domains of human recombinant phosphodiesterase 4A: structural requirements for catalytic activity and rolipram binding. Mol Pharmacol 50:891–899
Jarvest RL, Lowe G, Baraniak J, Stec WJ (1982) A stereochemical investigation of the hydrolysis of cyclic AMP and the (Sp)-and (Rp)-diastereoisomers of adenosine cyclic 3′:5′-phosphorothioate by bovine heart and baker’s-yeast cyclic AMP phosphodiesterases. Biochem J 203:461–470
Jeon KI, Xu X, Aizawa T, Lim JH, Jono H, Kwon DS, Abe J, Berk BC, Li JD, Yan C (2010) Vinpocetine inhibits NF-kappaB-dependent inflammation via an IKK-dependent but PDE-independent mechanism. Proc Natl Acad Sci USA 107:9795–9800
Jin SL, Swinnen JV, Conti M (1992) Characterization of the structure of a low Km, rolipram-sensitive cAMP phosphodiesterase. Mapping of the catalytic domain. J Biol Chem 267:18929–18939
Jin SC, Richard FJ, Kuo WP, D’Ercole AJ, Conti M (1999) Impaired growth and fertility of cAMP-specific phosphodiesterase PDE4D- deficient mice. Proc Natl Acad Sci USA 96:11998–12003
Juilfs DM, Fülle HJ, Zhao AZ, Houslay MD, Garbers DL, Beavo JA (1997) A subset of olfactory neurons that selectively express cGMP-stimulated phosphodiesterase (PDE2) and guanylyl cyclase-D define a unique olfactory signal transduction pathway. Proc Natl Acad Sci USA 94:3388–3395
Kalgutkar AS, Choo E, Taylor TJ, Marfat A (2004) Disposition of CP-671, 305, a selective phosphodiesterase 4 inhibitor in preclinical species. Xenobiotica 34:755–770
Kambayashi J, Liu Y, Sun B, Shakur Y, Yoshitake M, Czerwiec F (2003) Cilostazol as a unique antithrombotic agent. Curr Pharm Des 9:2289–2302
Kambayashi J, Shakur Y, Liu Y (2006) Bench to bedside: multiple actions of the PDE3 inhibitor cilostazol. In: Beavo JA, Francis SH, Houslay MD (eds) Cyclic nucleotide phosphodiesterases in health and disease. CRC Press, Boca Raton, pp 627–648
Kang KK, Ahn GJ, Sohn YS, Ahn BO, Kim WB (2003) DA-8159, a new PDE5 inhibitor, attenuates the development of compensatory right ventricular hypertrophy in a rat model of pulmonary hypertension. J Int Med Res 31:517–528
Kass DA, Champion HC, Beavo JA (2007) Phosphodiesterase type 5: expanding roles in cardiovascular regulation. Circ Res 101:1084–1095
Ke H, Wang EH (2007a) Structure, catalytic mechanism, and inhibitor selectivity of cyclic nucleotide phosphodiesterases. In: Beavo JA, Francis SH, Houslay MD (eds) Cyclic nucleotide phosphodiesterases in health and disease. Taylor & Francis Group, LLC, Boca Raton, pp 607–626
Ke H, Wang H (2007b) Crystal structures of phosphodiesterases and implications on substrate specificity and inhibitor selectivity. Curr Top Med Chem 7:391–403
Keravis T, Lugnier C (2010) Cyclic nucleotide phosphodiesterases (PDE) and peptide motifs. Curr Pharm Des 16(9):1114–1125
Kim D, Rybalkin SD, Pi X, Wang Y, Zhang C, Munzel T, Beavo JA, Berk BC, Yan C (2001) Upregulation of phosphodiesterase 1A1 expression is associated with the development of nitrate tolerance. Circulation 104:2338–2343
Klabunde RE (1983) Dipyridamole inhibition of adenosine metabolism in human blood. Eur J Pharmacol 93:21–26
Kobayashi M, Nasuhara Y, Betsuyaku T, Shibuya E, Tanino Y, Tanino M, Takamura K, Nagai K, Hosokawa T, Nishimura M (2004) Effect of low-dose theophylline on airway inflammation in COPD. Respirology 9:249–254
Laliberte F, Han Y, Govindarajan A, Giroux A, Liu S, Bobechko B, Lario P, Bartlett A, Gorseth E, Gresser M, Huang Z (2000) Conformational difference between PDE4 apoenzyme and holoenzyme. Biochemistry 39:6449–6458
Laliberte F, Liu S, Gorseth E, Bobechko B, Bartlett A, Lario P, Gresser MJ, Huang Z (2002) In vitro PKA phosphorylation-mediated human PDE4A4 activation. FEBS Lett 512:205–208
Li X, Baillie GS, Houslay MD (2009) Mdm2 directs the ubiquitination of βarrestin-sequestered cAMP phosphodiesterase-4D5. J Biol Chem 284:16170–16182
Lim J, Pahlke G, Conti M (1999) Activation of the cAMP-specific phosphodiesterase PDE4D3 by phosphorylation. Identification and function of an inhibitory domain. J Biol Chem 274:19677–19685
Liu S, Mansour MN, Dillman KS, Perez JR, Danley DE, Aeed PA, Simons SP, Lemotte PK, Menniti FS (2008) Structural basis for the catalytic mechanism of human phosphodiesterase 9. Proc Natl Acad Sci USA 105:13309–13314
Livi GP, Kmetz P, McHale MM, Cieslinski LB, Sathe GM, Taylor DP, Davis RL, Torphy TJ, Balcarek JM (1990) Cloning and expression of cDNA for a human low-Km, rolipram- sensitive cyclic AMP phosphodiesterase. Mol Cell Biol 10:2678–2686
Lukowski R, Rybalkin SD, Loga F, Leiss V, Beavo JA, Hofmann F (2010) Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes. Proc Natl Acad Sci USA 107:5646–5651
Lynch MJ, Baillie GS, Mohamed A, Li X, Maisonneuve C, Klussmann E, van Heeke G, Houslay MD (2005) RNA Silencing Identifies PDE4D5 as the Functionally Relevant cAMP Phosphodiesterase Interacting with {beta}Arrestin to Control the Protein Kinase A/AKAP79-mediated Switching of the {beta}2-Adrenergic Receptor to Activation of ERK in HEK293B2 Cells. J Biol Chem 280:33178–33189
MacFarland RT, Zelus BD, Beavo JA (1991) High concentrations of a cGMP-stimulated phosphodiesterase mediate ANP-induced decreases in cAMP and steroidogenesis in adrenal glomerulosa cells. J Biol Chem 266:136–142
Martinez SE, Beavo JA, Hol WG (2002a) GAF domains: two billion year old molecular switches that bind cyclic nucleotides. Mol Interv 2:317–323
Martinez SE, Wu AY, Glavas NA, Tang XB, Turley S, Hol WG, Beavo JA (2002b) The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding. Proc Natl Acad Sci USA 99:13260–13265
Martinez SE, Bruder S, Schultz A, Zheng N, Schultz JE, Beavo JA, Linder JU (2005) Crystal structure of the tandem GAF domains from a cyanobacterial adenylyl cyclase: modes of ligand binding and dimerization. Proc Natl Acad Sci USA 102:3082–3087
Martinez SE, Heikaus CC, Klevit RE, Beavo JA (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 283:25913–25919
McCahill A, McSorley T, Huston E, Hill EV, Lynch MJ, Gall I, Keryer G, Lygren B, Tasken K, van Heeke G, Houslay MD (2005) In resting COS1 cells a dominant negative approach shows that specific, anchored PDE4 cAMP phosphodiesterase isoforms gate the activation, by basal cyclic AMP production, of AKAP-tethered protein kinase A type II located in the centrosomal region. Cell Signal 17:1158–1173
McPhee I, Yarwood SJ, Huston E, Scotland G, Beard MB, Ross AH, Houslay ES, Houslay MD (1999) Association with the src family tyrosyl kinase LYN triggers a conformational change in the catalytic region of human cAMP-specific phosphodiesterase HSPDE4A4B: consequences for rolipram inhibition. J Biol Chem 274:11796–11810
Mery PF, Pavoine C, Pecker F, Fischmeister R (1995) Erythro-9-(2-hydroxy-3-nonyl)adenine inhibits cyclic GMP-stimulated phosphodiesterase in isolated cardiac myocytes. Mol Pharmacol 48:121–130
Miller CL, Oikawa M, Cai Y, Wojtovich AP, Nagel DJ, Xu X, Xu H, Florio V, Rybalkin SD, Beavo JA, Chen YF, Li JD, Blaxall BC, Abe J, Yan C (2009) Role of Ca2+/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy. Circ Res 105:956–964
Mongillo M, McSorley T, Evellin S, Sood A, Lissandron V, Terrin A, Huston E, Hannawacker A, Lohse MJ, Pozzan T, Houslay MD, Zaccolo M (2004) Fluorescence resonance energy transfer-based analysis of cAMP dynamics in live neonatal rat cardiac myocytes reveals distinct functions of compartmentalized phosphodiesterases. Circ Res 95:67–75
Mongillo M, Tocchetti CG, Terrin A, Lissandron V, Cheung Y-F, Dostmann WR, Pozzan T, Kass DA, Paolocci N, Houslay MD, Zaccolo M (2006) Compartmentalised phosphodiesterase-2 (PDE2) activity blunts β-adrenergic cardiac inotropy via a β3-adrenoceptor/NO/cGMP dependent pathway. Circ Res 98:226–234
Mullershausen F, Russwurm M, Friebe A, Koesling D (2004) Inhibition of phosphodiesterase type 5 by the activator of nitric oxide-sensitive guanylyl cyclase BAY 41-2272. Circulation 109:1711–1713
Murdoch H, Mackie S, Collins DM, Hill EV, Bolger GB, Klussmann E, Porteous DJ, Millar JK, Houslay MD (2007) Isoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels. J Neurosci 27:9513–9524
Nagayama T, Zhang M, Hsu S, Takimoto E, Kass DA (2008) Sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil. J Pharmacol Exp Ther 326:380–387
Obernolte R, Bhakta S, Alvarez R, Bach C, Zuppan P, Mulkins M, Jarnagin K, Shelton ER (1993) The cDNA of a human lymphocyte cyclic-AMP phosphodiesterase (PDE IV) reveals a multigene family. Gene 129:239–247
Ohshiro H, Tonai-Kachi H, Ichikawa K (2008) GPR35 is a functional receptor in rat dorsal root ganglion neurons. Biochem Biophys Res Commun 365:344–348
Omburo GA, Jacobitz S, Torphy TJ, Colman RW (1998) Critical role of conserved histidine pairs HNXXH and HDXXH in recombinant human phosphodiesterase 4A. Cell Signal 10:491–497
Omori K, Kotera J (2006) PDE11. In: Beavo JA, Francis SH, Houslay MD (eds) Cyclic nucleotide phosphodiesterases in health and disease. CRC Press, Boca Raton, pp 255–274
Omori K, Kotera J (2007) Overview of PDEs and their regulation. Circ Res 100:309–327
Owen DR, Walker JK, Jon Jacobsen E, Freskos JN, Hughes RO, Brown DL, Bell AS, Brown DG, Phillips C, Mischke BV, Molyneaux JM, Fobian YM, Heasley SE, Moon JB, Stallings WC, Joseph Rogier D, Fox DN, Palmer MJ, Ringer T, Rodriquez-Lens M, Cubbage JW, Blevis-Bal RM, Benson AG, Acker BA, Maddux TM, Tollefson MB, Bond BR, Macinnes A, Yu Y (2009) Identification, synthesis and SAR of amino substituted pyrido[3, 2b]pyrazinones as potent and selective PDE5 inhibitors. Bioorg Med Chem Lett 19:4088–4091
Pandit J, Forman MD, Fennell KF, Dillman KS, Menniti FS (2009) Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc Natl Acad Sci USA 106:18225–18230
Penmatsa H, Zhang W, Yarlagadda S, Li C, Conoley VG, Yue J, Bahouth SW, Buddington RK, Zhang G, Nelson DJ, Sonecha MD, Manganiello V, Wine JJ, Naren AP (2010) Compartmentalized cyclic adenosine 3′, 5′-monophosphate at the plasma membrane clusters PDE3A and cystic fibrosis transmembrane conductance regulator into microdomains. Mol Biol Cell 21:1097–1110
Poppe H, Rybalkin SD, Rehmann H, Hinds TR, Tang XB, Christensen AE, Schwede F, Genieser HG, Bos JL, Doskeland SO, Beavo JA, Butt E (2008) Cyclic nucleotide analogs as probes of signaling pathways. Nat Methods 5:277–278
Puxeddu E, Uhart M, Li CC, Ahmad F, Pacheco-Rodriguez G, Manganiello VC, Moss J, Vaughan M (2009) Interaction of phosphodiesterase 3A with brefeldin A-inhibited guanine nucleotide-exchange proteins BIG1 and BIG2 and effect on ARF1 activity. Proc Natl Acad Sci USA 106:6158–6163
Rabe KF, Magnussen H, Dent G (1995) Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants. Eur Respir J 8:637–642
Rich TC, Fagan KA, Tse TE, Schaack J, Cooper DM, Karpen JW (2001a) A uniform extracellular stimulus triggers distinct cAMP signals in different compartments of a simple cell. Proc Natl Acad Sci USA 98:13049–13054
Rich TC, Tse TE, Rohan JG, Schaack J, Karpen JW (2001b) In vivo assessment of local phosphodiesterase activity using tailored cyclic nucleotide-gated channels as cAMP sensors. J Gen Physiol 118:63–78
Rich TC, Xin W, Mehats C, Hassell KA, Piggott L, Le X, Karpen JW, Conti M (2006) Cellular mechanisms underlying prostaglandin-induced transient cAMP signals near the plasma membrane of HEK-293 cells. Am J Physiol Cell Physiol 292:C319–C331
Richter W, Conti M (2002) Dimerization of the type 4 cAMP-specific phosphodiesterases is mediated by the upstream conserved regions (UCRs). J Biol Chem 277:40212–40221
Richter W, Conti M (2004) The oligomerization state determines regulatory properties and inhibitor sensitivity of type 4 cAMP-specific phosphodiesterases. J Biol Chem 279:30338–30348
Rocque WJ, Holmes WD, Patel IR, Dougherty RW, Ittoop O, Overton L, Hoffman CR, Wisely GB, Willard DH, Luther MA (1997) Detailed characterization of a purified type 4 phosphodiesterase, HSPDE4B2B: differentiation of high- and low-affinity (R)-rolipram binding. Protein Exp Purif 9:191–202
Rybalkin SD, Bornfeldt KE, Sonnenburg WK, Rybalkina IG, Kwak KS, Hanson K, Krebs EG, Beavo JA (1997) Calmodulin-stimulated cyclic nucleotide phosphodiesterase (PDE1C) is induced in human arterial smooth muscle cells of the synthetic, proliferative phenotype. J Clin Invest 100:2611–2621
Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA (2003) Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 93:280–291
Rybalkina IG, Tang XB, Rybalkin SD (2010) Multiple affinity states of cGMP-specific phosphodiesterase for sildenafil inhibition defined by cGMP-dependent and cGMP-independent mechanisms. Mol Pharmacol 77:670–677
Salanova M, Jin SC, Conti M (1998) Heterologous expression and purification of recombinant rolipram-sensitive cyclic AMP-specific phosphodiesterases. Methods 14:55–64
Saldou N, Baecker PA, Li B, Yuan Z, Obernolte R, Ratzliff J, Osen E, Jarnagin K, Shelton ER (1998) Purification and physical characterization of cloned human cAMP phosphodiesterases PDE-4D and -4C. Cell Biochem Biophys 28:187–217
Scapin G, Patel SB, Chung C, Varnerin JP, Edmondson SD, Mastracchio A, Parmee ER, Singh SB, Becker JW, Van der Ploeg LH, Tota MR (2004) Crystal structure of human phosphodiesterase 3B: atomic basis for substrate and inhibitor specificity. Biochemistry 43:6091–6100
Schaper W (2005) Dipyridamole, an underestimated vascular protective drug. Cardiovasc Drugs Ther 19:357–363
Schultz JE, Dunkern T, Gawlitta-Gorka E, Sorg G (2011) The GAF-tandem domain of phosphodiesterase 5 as a potential drug target. Francis SH, Conti M, HouslayMD (eds) Phosphodiesterases as drug targets. Springer, Heidelberg
Scotland G, Houslay MD (1995) Chimeric constructs show that the unique N-terminal domain of the cyclic AMP phosphodiesterase RD1 (rPDE-IVA1;RNPDE4A1A) can confer membrane association upon the normally cytosolic protein chloramphenicol acetyl transferase (CAT). Biochem J 308:673–681
Sekhar KR, Grondin P, Francis SH, Corbin JD (1996) Design and synthesis of xanthines and cyclic GMP analogues as potent inhibitors of PDE5. In: Schudt C, Dent G, Rabe KF (eds) Phosphodiesterase inhibitors. Academic, New York, pp 135–146
Serebruany V, Sabaeva E, Booze C, Atar OD, Eisert C, Hanley D (2009) Distribution of dipyridamole in blood components among post-stroke patients treated with extended release formulation. Thromb Haemost 102:538–543
Sette C, Conti M (1996) Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase. Involvement of serine 54 in the enzyme activation. J Biol Chem 271:16526–16534
Shakur Y, Pryde J, Houslay MD (1993) Engineered deletion of the unique N–terminal domain of the cyclic AMP specific phosphodiesterase RD1 prevents plasma membrane association and the attainment of enhanced thermostability without altering its sensitivity to inhibition by rolipram. Biochem J 292:677–686
Smith KJ, Scotland G, Beattie J, Trayer IP, Houslay MD (1996) Determination of the structure of the N-terminal splice region of the cyclic AMP-specific phosphodiesterase RD1 (RNPDE4A1) by 1H-NMR and identification of the membrane association domain using chimeric constructs. J Biol Chem 271:16703–16711
Smith KJ, Baillie GS, Hyde EI, Li X, Houslay TM, McCahill A, Dunlop AJ, Bolger GB, Klussmann E, Adams DR, Houslay MD (2007) 1H NMR structural and functional characterisation of a cAMP-specific phosphodiesterase-4D5 (PDE4D5) N-terminal region peptide that disrupts PDE4D5 interaction with the signalling scaffold proteins, beta-arrestin and RACK1. Cell Signal 19:2612–2624
Souness JE, Rao S (1997) Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases. Cell Signal 9:227–236
Stasch JP, Hobbs AJ (2009) NO-independent, haem-dependent soluble guanylate cyclase stimulators. Handb Exp Pharmacol 191:277–308
Steinberg SF, Brunton LL (2001) Compartmentation of G protein-coupled signaling pathways in cardiac myocytes. Annu Rev Pharmacol Toxicol 41:751–773
Sudo T, Tachibana K, Toga K, Tochizawa S, Inoue Y, Kimura Y, Hidaka H (2000) Potent effects of novel anti-platelet aggregatory cilostamide analogues on recombinant cyclic nucleotide phosphodiesterase isozyme activity. Biochem Pharmacol 59:347–356
Sullivan M, Egerton M, Shakur Y, Marquardsen A, Houslay MD (1994) Molecular cloning and expression, in both COS-1 cells and S. cerevisiae, of a human cytosolic type-IVA, cyclic AMP specific phosphodiesterase (hPDE-IVA-h6.1). Cell Signal 6:793–812
Sung BJ, Hwang KY, Jeon YH, Lee JI, Heo YS, Kim JH, Moon J, Yoon JM, Hyun YL, Kim E, Eum SJ, Park SY, Lee JO, Lee TG, Ro S, Cho JM (2003) Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. Nature 425:98–102
Takimoto E, Champion HC, Belardi D, Moslehi J, Mongillo M, Mergia E, Montrose DC, Isoda T, Aufiero K, Zaccolo M, Dostmann WR, Smith CJ, Kass DA (2005a) cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism. Circ Res 96:100–109
Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA (2005b) Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11:214–222
Taniguchi Y, Tonai-Kachi H, Shinjo K (2006) Zaprinast, a well-known cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, is an agonist for GPR35. FEBS Lett 580:5003–5008
Tasken KA, Collas P, Kemmner WA, Witczak O, Conti M, Tasken K (2001) Phosphodiesterase 4D and protein kinase a type II constitute a signaling unit in the centrosomal area. J Biol Chem 276:21999–22002
Tenor H, Hatzelmann A, Beume R, Lahu G, Zech K, Bethke TD (2011) Pharmacology, clinical efficacy and tolerability of PDE4 inhibitors: Impact of human pharmacokinetics. Francis SH, Conti M, HouslayMD (eds) Phosphodiesterases as drug targets. Springer, Heidelberg
Thomas MK, Francis SH, Beebe SJ, Gettys TW, Corbin JD (1992) Partial mapping of cyclic nucleotide sites and studies of regulatory mechanisms of phosphodiesterases using cyclic nucleotide analogues. Adv Second Messenger Phosphoprotein Res 25:45–53
Thompson WJ (1991) Cyclic nucleotide phosphodiesterases: pharmacology, biochemistry and function. Pharmacol Ther 51:13–33
Tian G, Rocque WJ, Wiseman JS, Thompson IZ, Holmes WD, Domanico PL, Stafford JA, Feldman PL, Luther MA (1998) Dual inhibition of human type 4 phosphodiesterase isostates by (R, R)-(+/-)-methyl 3-acetyl-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-3- methyl-1-pyrrolidinecarboxylate. Biochemistry 37:6894–6904
Toque HA, Teixeira CE, Priviero FB, Morganti RP, Antunes E, De Nucci G (2008) Vardenafil, but not sildenafil or tadalafil, has calcium-channel blocking activity in rabbit isolated pulmonary artery and human washed platelets. Br J Pharmacol 154:787–796
Torphy TJ (1998) Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 157:351–370
Trifilieff A, Wyss D, Walker C, Mazzoni L, Hersperger R (2002) Pharmacological profile of a novel phosphodiesterase 4 inhibitor, 4-(8-benzo[1, 2, 5]oxadiazol-5-yl-[1, 7]naphthyridin-6-yl)-benzoic acid (NVP-ABE171), a 1, 7-naphthyridine derivative, with anti-inflammatory activities. J Pharmacol Exp Ther 301:241–248
Turko IV, Ballard SA, Francis SH, Corbin JD (1999) Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. Mol Pharmacol 56:124–130
Uhler MD (1993) Cloning and expression of a novel cyclic GMP-dependent protein kinase from mouse brain. J Biol Chem 268:13586–13591
Vandeput F, Krall J, Ockaili R, Salloum FN, Florio V, Corbin JD, Francis SH, Kukreja RC, Movsesian MA (2009) cGMP-hydrolytic activity and its inhibition by sildenafil in normal and failing human and mouse myocardium. J Pharmacol Exp Ther 330:884–891
Verhoest PR, Chapin DS, Corman M, Fonseca K, Harms JF, Hou X, Marr ES, Menniti FS, Nelson F, O’Connor R, Pandit J, Proulx-Lafrance C, Schmidt AW, Schmidt CJ, Suiciak JA, Liras S (2009) Discovery of a Novel Class of Phosphodiesterase 10A Inhibitors and Identification of Clinical Candidate 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the Treatment of Schizophrenia (dagger) dagger Coordinates of the PDE10A crystal structures have been deposited in the Protein Data Bank for compound 1 (3HQW), 2 (3HQY), 3 (3HQW) and 9 (3HR1). J Med Chem 52:5188
Walseth TF, Gander JE, Eide SJ, Krick TP, Goldberg ND (1983) 18O labeling of adenine nucleotide alpha-phosphoryls in platelets. Contribution by phosphodiesterase-catalyzed hydrolysis of cAMP. J Biol Chem 258:1544–1558
Wang P, Myers JG, Wu P, Cheewatrakoolpong B, Egan RW, Billah MM (1997) Expression, purification, and characterization of human cAMP-specific phosphodiesterase (PDE4) subtypes A, B, C, and D. Biochem Biophys Res Commun 234:320–324
Wang H, Liu Y, Chen Y, Robinson H, Ke H (2005) Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7. J Biol Chem 280:30949–30955
Wang H, Liu Y, Hou J, Zheng M, Robinson H, Ke H (2007) Structural insight into substrate specificity of phosphodiesterase 10. Proc Natl Acad Sci USA 3;104:5782–5787
Wang H, Liu Y, Huai Q, Cai J, Zoraghi R, Francis SH, Corbin JD, Robinson H, Xin Z, Lin G, Ke H (2006) Multiple conformations of phosphodiesterase-5: implications for enzyme function and drug development. J Biol Chem 281:21469–21479
Wang H, Peng MS, Chen Y, Geng J, Robinson H, Houslay MD, Cai J, Ke H (2007) Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors. Biochem J 408:193–201
Wang H, Yan Z, Yang S, Cai J, Robinson H, Ke H (2008) Kinetic and structural studies of phosphodiesterase-8A and implication on the inhibitor selectivity. Biochemistry 47:12760–12768
Wang H, Ye M, Robinson H, Francis SH, Ke H (2008) Conformational variations of both phosphodiesterase-5 and inhibitors provide the structural basis for the physiological effects of vardenafil and sildenafil. Mol Pharmacol 73:104–110
Weeks JL 2nd, Zoraghi R, Francis SH, Corbin JD (2007) N-Terminal domain of phosphodiesterase-11A4 (PDE11A4) decreases affinity of the catalytic site for substrates and tadalafil, and is involved in oligomerization. Biochemistry 46:10353–10364
Wernet W, Flockerzi V, Hofmann F (1989) The cDNA of the two isoforms of bovine cGMP-dependent protein kinase. FEBS Lett 251:191–196
Wilson LS, Elbatarny HS, Crawley SW, Bennett BM, Maurice DH (2008) Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows selective cGMP-mediated regulation of platelet functions. Proc Natl Acad Sci USA 105:13650–13655
Wu AY, Tang XB, Martinez SE, Ikeda K, Beavo JA (2004) Molecular determinants for cyclic nucleotide binding to the regulatory domains of phosphodiesterase 2A. J Biol Chem 279:37928–37938
Xu RX, Hassell AM, Vanderwall D, Lambert MH, Holmes WD, Luther MA, Rocque WJ, Milburn MV, Zhao Y, Ke H, Nolte RT (2000) Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity. Science 288:1822–1825
Xu RX, Rocque WJ, Lambert MH, Vanderwall DE, Luther MA, Nolte RT (2004) Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP, and rolipram. J Mol Biol 337:355–365
Yamamoto T, Yamamoto S, Osborne JC Jr, Manganiello VC, Vaughan M, Hidaka H (1983) Complex effects of inhibitors on cyclic GMP-stimulated cyclic nucleotide phosphodiesterase. J Biol Chem 258:14173–14177
Yan C, Zhao AZ, Bentley JK, Beavo JA (1996) The calmodulin-dependent phosphodiesterase gene PDE1C encodes several functionally different splice variants in a tissue-specific manner. J Biol Chem 271:25699–25706
Yarwood SJ, Steele MR, Scotland G, Houslay MD, Bolger GB (1999) The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform. J Biol Chem 274:14909–14917
Zaccolo M, Pozzan T (2002) Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science 295:1711–1715
Zhang KYJ (2006) Crystal structure of phosphodiesterase families and the potential for rational drug design. In: Beavo J, Francis SH, Houslay MD (eds) Cyclic nucleotide phosphodiesterase in health and disease. CRC Press, Boca Raton, pp 583–605
Zhang W, Ke H, Colman RW (2002) Identification of interaction sites of cyclic nucleotide phosphodiesterase type 3A with milrinone and cilostazol using molecular modeling and site-directed mutagenesis. Mol Pharmacol 62:514–520
Zhang X, Feng Q, Cote RH (2005) Efficacy and selectivity of phosphodiesterase-targeted drugs in inhibiting photoreceptor phosphodiesterase (PDE6) in retinal photoreceptors. Invest Ophthalmol Vis Sci 46:3060–3066
Zhang XJ, Skiba NP, Cote RH (2009) Structural requirements of the photoreceptor phosphodiesterase {gamma}-subunit for inhibition of rod PDE6 holoenzyme and for its activation by transducin. J Biol Chem 285:4455–4463
Zhao Y, Zhang HT, O’Donnell JM (2003) Inhibitor binding to type 4 phosphodiesterase (PDE4) assessed using [3H]piclamilast and [3H]rolipram. J Pharmacol Exp Ther 305:565–572
Zhu B, Strada SJ (2007) The novel functions of cGMP-specific phosphodiesterase 5 and its inhibitors in carcinoma cells and pulmonary/cardiovascular vessels. Curr Top Med Chem 7:437–454
Zoraghi R, Corbin JD, Francis SH (2004) Properties and functions of GAF domains in cyclic nucleotide phosphodiesterases and other proteins. Mol Pharmacol 65:267–278
Zoraghi R, Bessay EP, Corbin JD, Francis SH (2005) Structural and functional features in human PDE5A1 regulatory domain that provide for allosteric cGMP binding, dimerization, and regulation. J Biol Chem 280:12051–12063
Zoraghi R, Francis SH, Corbin JD (2007) Critical amino acids in phosphodiesterase-5 catalytic site that provide for high-affinity interaction with cGMP and inhibitors. Biochemistry 46:13554–13563
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Francis, S.H., Houslay, M.D., Conti, M. (2011). Phosphodiesterase Inhibitors: Factors That Influence Potency, Selectivity, and Action. In: Francis, S., Conti, M., Houslay, M. (eds) Phosphodiesterases as Drug Targets. Handbook of Experimental Pharmacology, vol 204. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-17969-3_2
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