Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Miguel J. LoboEmail author
  • Manuela Zaccolo
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101603


Historical Background

Half a decade ago, the cyclic nucleotides cyclic adenosine 3′, 5′-monophosphate (cAMP) and cyclic guanosine 3′, 5′-monophosphate (cGMP) were identified as key second messenger molecules that mediate the intracellular effects of many signals known as “first messengers,” such as hormones or neurotransmitters. cAMP and cGMP signaling pathways regulate a vast number of physiological processes, including cell proliferation and differentiation, gene expression, apoptosis, and several metabolic processes, such as insulin secretion, glycogen synthesis, or lipogenesis. After their discovery, many years elapsed before cyclic nucleotides signaling proved to be a selective and effective process to modulate biological pathways. Since then, it has become clear that signaling by cyclic nucleotides modulates a countless number of biological functions, thus requiring a thigh control of their...

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  1. Acin-Perez R, Russwurm M, Günnewig K, Gertz M, Zoidl G, Ramos L, et al. A phosphodiesterase 2A isoform localized to mitochondria regulates respiration. J Biol Chem. 2011;286(35):30423–32.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Aye T-T, Soni S, van Veen TAB, van der Heyden MAG, Cappadona S, Varro A, et al. Reorganized PKA-AKAP associations in the failing human heart. J Mol Cell Cardiol. 2012;52(2):511–8.CrossRefPubMedGoogle Scholar
  3. Azevedo MF, Faucz FR, Bimpaki E, Horvath A, Levy I, de Alexandre RB, et al. Clinical and molecular genetics of the phosphodiesterases (PDEs). Endocr Rev. 2014;35(2):195–233.CrossRefPubMedGoogle Scholar
  4. Boess FG, Hendrix M, van der Staay F-J, Erb C, Schreiber R, van Staveren W, et al. Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology. 2004;47(7):1081–92.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Francis SH, Corbin JD, Bischoff E. Cyclic GMP-hydrolyzing phosphodiesterases. Handb Exp Pharmacol. 2009;191:367–408.CrossRefGoogle Scholar
  6. Gasser C, Taiber S, Yeh C-M, Wittig CH, Hegemann P, Ryu S, et al. Engineering of a red-light-activated human cAMP/cGMP-specific phosphodiesterase. Proc Natl Acad Sci U S A. 2014;111(24):8803–8.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Gomez L, Breitenbucher JG. PDE2 inhibition: potential for the treatment of cognitive disorders. Bioorg Med Chem Lett. 2013;23(24):6522–7.CrossRefPubMedGoogle Scholar
  8. Martins TJ, Mumby MC, Beavo JA. Purification and characterization of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase from bovine tissues. J Biol Chem. 1982;257(4):1973–9.PubMedGoogle Scholar
  9. Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC. Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov. 2014;13(4):290–314.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Morita H, Murata T, Shimizu K, Okumura K, Inui M, Tagawa T. Characterization of phosphodiesterase 2A in human malignant melanoma PMP cells. Oncol Rep. 2013;29(4):1275–84.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Pandit J, Forman MD, Fennell KF, Dillman KS, Menniti FS. 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. 2009;106(43):18225–30.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Russwurm C, Zoidl G, Koesling D, Russwurm M. Dual acylation of PDE2A splice variant 3: targeting to synaptic membranes. J Biol Chem. 2009;284(38):25782–90.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Stephenson DT, Coskran TM, Wilhelms MB, Adamowicz WO, O’Donnell MM, Muravnick KB, et al. Immunohistochemical localization of phosphodiesterase 2A in multiple mammalian species. J Histochem Cytochem Off J Histochem Soc. 2009;57(10):933–49.CrossRefGoogle Scholar
  14. Vettel C, Lämmle S, Ewens S, Cervirgen C, Emons J, Ongherth A, et al. PDE2-mediated cAMP hydrolysis accelerates cardiac fibroblast to myofibroblast conversion and is antagonized by exogenous activation of cGMP signaling pathways. Am J Physiol Heart Circ Physiol. 2014;306(8):H1246–52.CrossRefPubMedGoogle Scholar
  15. Zaccolo M, Movsesian MA. cAMP and cGMP signaling cross-talk: role of phosphodiesterases and implications for cardiac pathophysiology. Circ Res. 2007;100(11):1569–78.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Zhang KYJ, Card GL, Suzuki Y, Artis DR, Fong D, Gillette S, et al. A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases. Mol Cell. 2004;15(2):279–86.CrossRefPubMedGoogle Scholar
  17. Zhu J, Yang Q, Dai D, Huang Q. X-ray crystal structure of phosphodiesterase 2 in complex with a highly selective, nanomolar inhibitor reveals a binding-induced pocket important for selectivity. J Am Chem Soc. 2013;135(32):11708–11.CrossRefPubMedGoogle Scholar
  18. Zoccarato A, Surdo NC, Aronsen JM, Fields LA, Mancuso L, Dodoni G, et al. Cardiac hypertrophy is inhibited by a local pool of cAMP regulated by phosphodiesterase 2. Circ Res. 2015;117(8):707–19.CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK