Thromb Haemost 1999; 82(02): 407-411
DOI: 10.1055/s-0037-1615860
Research Article
Schattauer GmbH

Cyclic Nucleotide Phosphodiesterases (PDEs): Diverse Regulators of Cyclic Nucleotide Signals and Inviting Molecular Targets for Novel Therapeutic Agents

V. C. Manganiello
1   Pulmonary Critical Care Medicine Branch, NHLBI, NIH, Bethesda, MD, USA
,
E. Degerman
2   Department of Cell and Molecular Biology, Lund University, Lund, SWEDEN
› Author Affiliations
Further Information

Publication History

Publication Date:
09 December 2017 (online)

Introduction

Cyclic adenosine 3’5’-monophosphate (cAMP) and cyclic guanosine 3’5’-monophoshpate (cGMP) are critical intracellular second-messengers involved in the transduction of a wide variety of extracellular stimuli, including peptide hormones, growth factors, cytokines, neurotransmitters and light. These messengers modulate many fundamental biological processes, including growth, differentiation, apoptosis, glycogenolysis, lipolysis, immune/inflammatory responses, etc.

By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases (PDEs) are important determinants in regulating the intracellular concentrations and, consequently, the biological actions of these second-messengers (Fig. 1). The advent of molecular genetics has revealed the extraordinary complexity and diversity of the mammalian PDE superfamily, which contains at least 10 highly regulated and structurally-related gene families (PDEs 1-10).1-8 As depicted in Figure 1, some PDEs are highly specific for hydrolysis of cAMP (PDEs 4,7,8), some are cGMP-specific (PDEs 5,6,9), and some exhibit mixed specificity (PDEs 1,2,3,10). Most gene families are comprised of more than one isogene (indicated by A-D in Table 1). At least 19 genes encoding more than 30 isoforms have been identified. PDE families differ with respect to their primary structures, sensitivity to specific inhibitors, tissue distribution, subcellular localization, and mechanisms of regulation (Table 1).2-6 Within individual families, different mRNAs are generated from the same gene by use of different transcription initiation sites or by alternative mRNA splicing. These variant PDE isoforms are often tissue-specific and selectively expressed in various tissues and cell types.2-6 The importance of cyclic nucleotide signaling in cell regulation and the molecular diversity of PDEs has presented targets for selective interventions and development of family-specific PDE inhibitors as therapeutic agents. This brief review will discuss some general characteristics of PDEs and then focus on the cellular biology and diverse functions of different PDE isoforms and their potential as therapeutic targets.

 
  • References

  • 1 Beavo J, Conti M, Heaslip RJ. Multiple cyclic nucleotide phosphodiesterases. Mol Pharmacol 1994; 46: 399-405.
  • 2 Torphy T. Phosphodiesterase isoenzymes: molecular targets for novel anti-asthma agents. Am J Respir Crit Care Med 1998; 157: 351-370.
  • 3 Dousa T. Cyclic-3’5’-Nucleotide phosphodiesterase isoenzymes in cell biology and pathophysiology of the kidney. Kidney Int 1999; 55: 29-62.
  • 4 Degerman E, Belfrage P, Manganiello VC. Structure, localization and regulation of cGMP-inhibited phosphodiesterase (PDE3). J Biol Chem 1997; 272: 6823-6826.
  • 5 Perry M, Higgs G. Chemotherapeutic potential of phosphodiesterase inhibitors. Curr Opin Chem Biol 1998; 2: 472-481.
  • 6 Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 1995; 75: 725-748.
  • 7 Soderling SH, Bayuga SJ, Beavo JA. Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. J Biol Chem 1998; 273: 15553-15558.
  • 8 Fisher DA, Smith JF, Pillai JS, St Dennis SH, Cheng J. Isolation and characterization of PDE9A, a novel cGMP-specific phosphodiesterase. J Biol Chem 1998; 273: 15559-15564.
  • 9 Houslay MD, Milligan G. Tailoring cAMP-signaling responses through isoform multiplicity. TIBS 1997; 22: 217-224.
  • 10 Chini C, Grande J, Chini E, Dousa TP. Compartmentalization of cAMP signaling by phosphodiesterase isoenzymes PDE3 and PDE4: regulation of superoxidation and mitogenesis. J Biol Chem 1997; 272: 9854-9859.
  • 11 Gillespie PG. Phosphodiesterases in visual transduction in rods and cones. In: Beavo JA, Houslay MD. ed. Phosphodiesterases: Structure, Regulation and Drug Action. John Wiley and Sons, Inc.; New York: 1990: 163-184.
  • 12 McLaughlin ME, Ehrhart TL, Berson EL, Dryja TP. Mutation spectrum of the gene encoding the β subunit of rod phosphodiesterase among patients with recessive retinitis pigmentosa. Proc Natl Acad Sci USA 1995; 92: 3249-3253.
  • 13 MacFarland RT, Zelus BD, Beavo JA. High concentrations of a cGMP-stimulated PDE mediate ANP-induced decreases in cAMP and steroidogenesis in adrenal glomerulosa. J Biol Chem 1991; 266: 136-142.
  • 14 Dickinson N, Jang EK, Haslam RJ. Activation of cGMP-stimulated phosphodiesterase by nitroprusside limits cAMP accumulation in human platelets: effects on platelet aggregation. Biochem J 1997; 323: 371-377.
  • 15 Ahmad F, Gao G, Wang L-M, Lanstrom TR, Degerman E, Pierce JH, Manganiello VC. IL-3 and IL-4 activate cyclic nucleotide phosphodiesterases 3 (PDE3) and 4 (PDE4) by different mechanisms in FDCP2 myeloid cells. J Immunol 1999; 162: 4864-4875.
  • 16 Conti M, Nemoz G, Sette C, Vicini E. Recent progress in understanding hormonal regulation of phosphodiesterases. Endocr Rev 1995; 16: 370-389.
  • 17 Zhao A, Bornfeldt K, Beavo JA. Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. J Clin Invest 1998; 5: 869-873.
  • 18 Tsafriri A, Chun SY, Zhang R, Hsush AJW, Conti M. Oocyte maturation involves compartmentalization and opposing changes in cAMP levels in follicular somatic and germ cells—studies using selective phosphodiesterase inhibitors. Dev. Biol 1996; 178: 393-402.
  • 19 Wijkander J, Landstrom TR, Manganiello VC, Belfrage P, Degerman E. Insulin-induced phosphorylation and activation of phosphodiesterase 3B in rat adipocytes: possible role for protein kinase B but not mitogen-activated protein kinase or p70S6 kinase. Endocrinology 1998; 139: 219-227.
  • 20 Pyne N, Cooper M, Houslay M. The insulin- and glucogen-stimulated “dense vesicle” high affinity cAMP phosphodiesterase from rat liver. Biochem J 1987; 242: 33-42.
  • 21 Andersen C, Roth R, Conti M. Protein kinase B/Akt induces resumption of meiosis in Xenopus oocytes . J Biol Chem 1998; 273: 31515-31525.
  • 22 Rybalkin SD, Bornfeldt K, Sonnenberg WK, Rybalkin IG, Kwak KS, Hanson K, Krebs EG, Beavo JA. Calmodulin-stimulated cyclic nucleotide phosphodiesterase (PDE1C) is induced in human arterial smooth muscle cells of the synthetic proliferative phenotype. J Clin Invest 1996; 100: 2611-2621.
  • 23 Komas N, Movsesian M, Kedev S, Degerman E, Belfrage P, Manganiello VC. cGMP-inhibited phosphodiesterases. In: Schudt C, Dent G, Rabe KF. eds. Phosphodiesterase Inhibitors. Academic Press; New York: 1996: 89-109.
  • 24 Souness JH, Hassall GA, Parrott DP. Inhibition of pig aortic smooth muscle cell DNA synthesis by selective type III and type IV cyclic AMP phosphodiesterase inhibitors. Biochem Pharmacol 1992; 44: 857-866.
  • 25 Pan X, Arauz E, Krzanowski JJ, Fitzpatrick DF, Polson JE. Synergistic interactions between selective pharmacological inhibitors of phosphodiesterase isoenzyme families PDEIII and PDEIV to attenuate proliferation of rat vascular smooth muscle cells. Biochem Pharmacol 1994; 48: 827-835.
  • 26 Johnson-Mills K, Arauz E, Coffey RG, Krzanowski JJ, Polson JB. Effects of CI-930 and Rolipram on human coronary artery smooth muscle cell proliferation. Biochem Pharmacol 1998; 56: 1065-1073.
  • 27 Giembycz M, Corrigan CJ, Seybold J, Newton R, Barnes P. Identification of cAMP phosphodiesterases 3, 4, and 7 in human CD4+ and CD8+ T-lymphocytes: role in regulating proliferation and the biosynthesis of interleukin-2. Br J Pharmacol 1966; 118: 1945-1948.
  • 28 Robicsek S, Blanchard D, Djeu J, Krzanowski J, Szentevanyi A, Polson J. Multiple high affinity cAMP phosphodiesterases in human T-lymphocytes. Biochem Pharmacol 1991; 42: 869-877.
  • 29 Marcos P, Prigent A, Lagarde M, Nemoz G. Modulation of rat thymocyte proliferative response through inhibition of different cyclic nucleotide phosphodiesterase isoforms by means of selective inhibitors and cGMP-elevating agents. Mol Pharmacol 1993; 44: 1027-1035.
  • 30 Li L, Yee C, Beavo JA. CD3- and CD28-dependent induction of PDE7 required for T-cell activation. Science 1999; 283: 848-851.
  • 31 Tenor N, Schudt C. Analysis of PDE isoenyzme profiles in cells and tissues by pharmacological methods. In: Schudt C, Dent G, Rabe KF. eds. Phosphodiesterase Inhibitors. Academic Press; New York: 1996: 21-40.
  • 32 Houslay MD, Sullivan M, Bolger GB. The multienzyme PDE4 cAMP-specific PDE family: intracellular targeting, regulation, and selective inhibition by compounds exerting anti-inflammatory and anti-depressant actions. Adv Pharmacol 1998; 44: 225-342.
  • 33 Silver P. Inhibition of phosphodiesterase isoenzymes and cell function by selective PDE5 inhibitors. In: Schudt C, Dent G, Rabe KF. eds. Phosphodiesterase Inhibitors. Academic Press; New York: 1996: 127-134.
  • 34 Cohen AH, Hanson K, Morris K, Fonty B, McMurty I, Clarke W, Rodman D. Inhibition of cGMP-specific phosphodiesterase selective vasodilates the pulmonary circulation in chronically hypoxic rats. J Clin Invest 1996; 97: 172-179.
  • 35 Liang L, Beshay E, Prud’homme GJ. The phosphodiesterase inhibitors pentoxifylline and rolipram prevent diabetes in mice. Diabetes 1998; 47: 570-575.
  • 36 Ross SE, Williams RO, Mason LJ, Mauri C, Marinova-Mutafchieva L, Malfort A-M, Maini R, Feldmann M. Suppression of TNFα expression, inhibition of Th1 activity and amelioration of collagen-induced arthritis by rolipram. J Immunol 1997; 159: 6253-6259.
  • 37 Sommer N, Loschmann PA, Northoff GH, Weller M, Steinbrecher A, Steinbach JP, Lichtenfels R, Myermann R, Reithmuller A, Fontana A, Dichgans J, Martin R. The antidepressant Rolipram ameliorates experimental autoimmune encephalomyelitis in Lewis rats. Nat Med 1995; 1: 244.
  • 38 DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant RC, Wright R. A comparison of oral Milrinone, Digoxin and their combination in treatment of patients with chronic heart failure. New Engl J Med 1998; 320: 677-683.
  • 39 Tsuchikane E, Katoh O, Sumitsuji S, Fukuhara A, Funamoto M, Otsuji H, Awata N, Kobayashi T. Impact of Cilostazol on intimal proliferation after directional coronary atherectomy. Am Heart J 1998; 135: 495-502.
  • 40 Boolell M, Allen MJ, Ballard SA, Gepi-Altee S, Murhead GJ, Naylor AM, Osterloh IH, Gingell C. Sildenafil, an orally active type 5 cGMP-specific phosphodiesterase inhibitor for the treatment of erectile dysfunction. Int J Impot Res 1996; 8: 47-52.